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Neuropharmacology xxx (2013) 1e10

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Neuropharmacology

journal homepage: www.elsevier .com/locate/neuropharm

Invited review

Neuron-specific chromatin remodeling: A missing link in epigeneticmechanisms underlying synaptic plasticity, memory, and intellectualdisability disorders

Annie Vogel-Ciernia a,b, Marcelo A. Wood a,b,*

aUniversity of California, Irvine, Department of Neurobiology & Behavior, Irvine, CA, USAbCenter for the Neurobiology of Learning & Memory, Irvine, CA, USA

a r t i c l e i n f o

Article history:Received 3 August 2013Received in revised form29 September 2013Accepted 4 October 2013

Keywords:Chromatin remodelingNucleosome remodelingEpigeneticsLong-term memoryLong-term potentiationIntellectual disability disorderAutism spectrum disorder

Abbreviations: CRC, chromatin remodeling complefactor; P-BAF, Polybromo-BAF; esBAF, embryonic steprogenitor BAF; nBAF, neuronal BAF; ID, intellectualtrum disorder; SZ, schizophrenia.* Corresponding author. University of California, Irv

ology & Behavior, Center for the Neurobiology of LearnResearch Labs, Irvine, CA 92697-3800, USA. Tel.: þ1 9

E-mail address: mwood@uci.edu (M.A. Wood).

0028-3908/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.neuropharm.2013.10.002

Please cite this article in press as: Vogel-mechanisms underlying synaptic plasticity10.1016/j.neuropharm.2013.10.002

a b s t r a c t

Long-term memory formation requires the coordinated regulation of gene expression. Until recentlynucleosome remodeling, one of the major epigenetic mechanisms for controlling gene expression, hadbeen largely unexplored in the field of neuroscience. Nucleosome remodeling is carried out by chromatinremodeling complexes (CRCs) that interact with DNA and histones to physically alter chromatin structureand ultimately regulate gene expression. Human exome sequencing and gene wide association studieshave linked mutations in CRC subunits to intellectual disability disorders, autism spectrum disorder andschizophrenia. However, how mutations in CRC subunits were related to human cognitive disorders wasunknown. There appears to be both developmental and adult specific roles for the neuron specific CRCnBAF (neuronal Brg1/hBrm Associated Factor). nBAF regulates gene expression required for dendriticarborization during development, and in the adult, contributes to long-term potentiation, a form ofsynaptic plasticity, and long-term memory. We propose that the nBAF complex is a novel epigeneticmechanism for regulating transcription required for long-lasting forms of synaptic plasticity and memoryprocesses and that impaired nBAF function may result in human cognitive disorders.

This article is part of a Special Issue entitled ‘Neuroepigenetic disorders’.� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Researchers have known for several decades that long-termmemory formation requires gene expression. Regulation of geneexpression following learning requires access to DNA, which ishighly compacted in chromatin (Alberini, 2009; Barrett and Wood,2008). The basic repeating unit of chromatin is the nucleosomethat consists of DNA wrapped around a histone octamer. Access tothe DNA is controlled by many factors including changes in histonetail modifications, DNA methylation and the actual movement ofnucleosomes along the DNA in a process called chromatin remod-eling (Barrett and Wood, 2008; Hargreaves and Crabtree, 2011). Todate the majority of the work on epigenetic regulation of gene

x; BAF, Brg1/hBrm associatedm cell BAF; npBAF, neuronaldisability; ASD, autism spec-

ine, Department of Neurobi-ing & Memory, 301 Qureshey49 824 2259.

All rights reserved.

Ciernia, A., Wood, M.A., Ne, memory, and intellectual

expression during memory formation has focused on histonemodifications (chromatin modification) and DNA methylation (seespecial issues in Neurobiology of Learning and Memory (2012) andNeuropsychopharmacology Reviews (2013)). Chromatin remodeling(not to be confused with chromatin modification), although widelystudied in fields outside of neuroscience, and had until recently onlybeen examined in neuroscience in the context of neuronal devel-opment in vitro. The importance of further exploring this majorepigenetic mechanism became increasingly apparent with recenthuman exome sequencing and genome wide association studiesimplicating mutations in components of the chromatin remodelingcomplex BAF (Brg1/hBrmAssociated Factor) in intellectual disabilitydisorders (Santen et al., 2012; Tsurusaki et al., 2012; VanHoudt et al.,2012), autism (Neale et al., 2012; O’Roak et al., 2012), and schizo-phrenia (Loe-Mie et al., 2010). It was unclear how the BAF subunitmutations were related to human cognitive deficits e were thedeficits simply a by-product of developmental abnormalities or wasthere an additional role for chromatin remodeling complexes (CRCs)in the adult brain? The answer appears to be complex with anidentified role for CRCs in both neuronal development and adultplasticity. This review will focus on the role of the neuron specificBAF complex (nBAF) in both neuronal development and long-term

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

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memory formation in the adult. Specifically, we propose that thenBAF complex is a novel epigenetic mechanism for regulatingtranscription required for long-lasting forms of synaptic plasticityandmemory processes and that impaired nBAF function may resultin human cognitive disorders.

2. Epigenetics in long-term memory formation

Many studies have recently focused on epigenetic mechanismsof transcriptional regulation in controlling gene expression un-derlying long-term memory formation (see special issues refer-enced above; and issues focused on this topic in this special issue ofNeuropharmacology). In a broad sense, epigenetics refers to theregulation of gene expression via chromatin structure that is in-dependent of changes in DNA sequence (Day and Sweatt, 2011;Vogel-Ciernia and Wood, 2012). There are at least five majorepigenetic mechanisms by which chromatin structure is regulatedto control gene expression: histone modification, histone variantinsertion, DNA methylation, noncoding RNAs, and chromatinremodeling.

The consolidation of new learning requires coordinatedexpression of specific profiles of gene targets (for review seeAlberini, 2009). Transcription initiation requires access to DNA fortranscription factor and RNA polymerase binding. Within eukary-otic cells DNA is highly compacted (w10,000 fold) into chromatin.The repeating unit of chromatin is the nucleosome that consists of147 base pairs of DNA wrapped around a histone octamer (canon-ically includes two of each of the following core histone proteins:H2A, H2B, H3, and H4)(Kouzarides, 2007). Histone variants can beincorporated into the nucleosome and may alter nucleosome sta-bility (ie. H3.3/H2A.Z incorporation at active promoters and en-hancers (Jin et al., 2009)). Nucleosomes are spaced approximatelyevery 10 to 50 base pairs, depending on the organism and cell type.At the entry and exit sites of the nucleosome core the DNA is boundby the linker histone H1 and under physiological conditions stringsof nucleosomes form higher order secondary (ie. 30 nm fiber) andtertiary structures (Clapier and Cairns, 2009).

Gaining access to regulatory regions of DNA (ie. promoters,enhancers and repressors regions) for transcriptional regulationcan require modification of the surrounding chromatin environ-ment including post translation modification of histone tails, DNAmethylation, histone variant insertion, nucleosome positioning,and alterations to higher order chromatin structure (e.g. chromo-somal looping (Jiang et al., 2010)). Post translation modification(phosphorylated, acetylated, methylated, etc) of histone tails canalter the interaction between DNA and the histone octamer, recruithistone or DNA-interacting proteins, and either promote or represstranscription (Bannister and Kouzarides, 2011). The regulation ofhistone modifications is one of the best studied epigenetic mech-anisms in learning and memory and has been extensively reviewedelsewhere (Barrett and Wood, 2008; Gräff and Tsai, 2013; Peixotoand Abel, 2013; Vogel-Ciernia and Wood, 2012). Another increas-ingly studied epigenetic mechanism in learning and memory isDNA methylation (Baker-Andresen et al., 2013; Su and Tsai, 2012;Zovkic et al., 2013). DNA methylation appears to play a criticalrole in long-term memory (Lubin et al., 2008; Miller et al., 2010;Miller and Sweatt, 2007) and long-term potentiation (Levensonet al., 2006). Experience dependent DNA methylation has beenproposed to alter the transcriptional response to subsequentlearning events serving as a form of cellular metaplasticity (forreview see Baker-Andresen et al., 2013). New evidence also pointsto a critical role for non-coding RNAs in regulating long-termmemory (Bredy et al., 2011; Landry et al., 2013) and drug addic-tion (Bali and Kenny, 2013). Histone variant insertion has beenlargely unstudied in the context of learning andmemory other than

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

work demonstrating a requirement for polyADP-ribosylation of H1for long-term memory formation in Aplysia (Cohen-Armon et al.,2004) and mammals (Goldberg et al., 2009). Until recently therole of CRCs in regulating long-term memory formation wascompletely unexplored. Given that this mechanism has receivedlittle attentionwithin the field of learning and memory, this reviewwill first provide a background on CRCs with a focus on BAF (Brg1/hBrm associated factor) complexes, one of the most highly studiedCRCs. We then focus on the role of the neuron-specific CRC nBAF inneuronal development, the link between BAF subunit mutationsand human cogitative disorders and finally on new work demon-strating a specific role for nBAF in long-term memory formationand synaptic plasticity.

3. Chromatin remodeling Complexesdsubunit combinatorialcomplexity

Chromatin remodeling complexes (CRCs) are large, multi pro-tein complexes that possess nucleosome and DNA-dependentATPase function. Chromatin remodeling complexes fall into fourlarge families depending on their ATPase: BAF (Brg1, hBrm), INO80/SWR1 (hINO80, hDomino, SRCAP), ISWI or NURF (hSNF2H,hSNF2L), and CHD or NuRD (CHD1-9) (Hargreaves and Crabtree,2011). Standard biochemical methods for examining CRC functionhave looked at nucleosome positioning using in vitro DNA tem-plates with artificially assembled nucleosome arrays. In general, inthese assays CRCs interact with DNA and nucleosomes and hydro-lyze ATP to disrupt nucleosome DNA contacts, slide nucleosomesalong DNA, and evict or exchange nucleosomes (Clapier and Cairns,2009; Hargreaves and Crabtree, 2011) (Fig.1). This reviewwill focuson the BAF complex (formerly called the mammalian SWI/SNFcomplex) since it is the only known chromatin remodeling complexto contain a neuron-specific subunit and is the most extensivelystudied CRC in regards to neuronal function in both developmentand the adult. The BAF complex was originally characterized as themammalian homolog of the yeast SWI/SNF complex (Kwon et al.,1994; Wang et al., 1996a). The complex is defined by a DNA-dependent ATPase subunit that is conserved across yeast (SWI2),Drosophila (brahma or brm), and mammals (Brg1 and hBrm)(Khavari et al., 1993; Muchardt and Yaniv, 1993). Across species thehomologous complexes share several characteristics includingsubunits with domains that recognize histone modifications, anATPase, and regulatory domains (Clapier and Cairns, 2009;Hargreaves and Crabtree, 2011).

Mammalian BAF complexes are composed of an assembly of atleast 15 subunits encoded by 28 genes (Ronan et al., 2013; Staahlet al., 2013) and contain either the Brg1 or hBrm ATPase.Mammalian BAF complexes exhibit evolutionary divergence fromthe yeast SWI/SNF complex in that 9 of the 15 BAF subunits do nothave yeast homologs and several BAF subunits have homologs innon-SWI/SNF yeast complexes. In addition to both the loss and gainof subunits over time, BAF complexes, unlike the yeast SWI/SNFcomplex, are combinatorally assembled. All identified BAF com-plexes have an ATPase (Brg1 or hBrm) and the following subunits:BAF47 (SMARCB1), BAF57 (SMARCE1), BAF60 (A, B, or C; SMARCD1,2, or 3), BAF155 (SMARCC1), BAF45 (A, B, C or D; PHF10, DPF1, 3 or2), BAF53 (A or B; ACTL6A or B), BAF250 (A or B) and monomericbeta-actin (Middeljans et al., 2012; Ronan et al., 2013) (see Fig. 2).Recent affinity purification and mass spectrometry based analysisof BAF complexes in several cell types expanded the BAF subunits toinclude BLC7A, BLC7B, BLC7C, BCL11A, BCL11B, BRD9, and SS18 (orSS18L1) (Kadoch et al., 2013; Kaeser et al., 2008; Middeljans et al.,2012). In addition the unique Polybromo BAF (P-BAF) (Lemon et al.,2001; Xue et al., 2000; Yan et al., 2005) complex is defined by thepresence of the BAF180 (polybromo) (Lemon et al., 2001; Wang

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

Fig. 1. Potential Roles for Chromatin Remodeling Complexes in Modifying Chromatin Structure. Based primarily on in vitro work done in the yeast homolog complex SWI/SNF, BAFcomplexes may play a key regulatory role in altering chromatin structure by any combination of the following: histone variant insertion, nucleosome sliding, nucleosome eviction,and chromatin looping or other higher order chromatin organization.

Fig. 2. Combinatorial Assembly of BAF Complexes. Unique BAF complexes are found in embryonic stem cells (esBAF), neuronal progenitors (npBAF), and neurons (nBAF). esBAF ischaracterized by a BAF155 dimer (no BAF170), Brg1, and BAF60a/b (without BAF60c) (white outline). During the transition from embryonic stem cells to neuronal progenitors esBAFis replaced by npBAF. In npBAF one of the BAF155 subunits is replaced with BAF170, BAF60 can be a, b, or c and Brm can serve as the ATPase (yellow outline). npBAF is alsocharacterized by the presence of SS18, BAF45a/d and BAF53a (white outline). During neuronal differentiation BAF53a is replaced by BAF53b, BAF45a/d is replaced by BAF45b/c, andSS18 is replaced by CREST (outlined in yellow). In nBAF the presence of BAF60b is also greatly reduced. The Polybromo BAF complex (P-BAF) is not shown here as a unique complexbut is defined by the inclusion of BAF180, BAF200, and Brd7 and the absence of BAF250A/B and Brd9.

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et al., 1996a; Xue et al., 2000), Brd7 (Kaeser et al., 2008) and BAF200(ARID2) (Wang et al., 1998; Xue et al., 2000; Yan et al., 2005) sub-units and a lack of BAF250A/B (ARID1A/B) (Lemon et al., 2001;Wang et al., 1998) and Brd9 (Middeljans et al., 2012). Altering thesubunit composition allows for an extensive diversity with bothtissue and cell-type specific roles depending on the specific BAFsubunit composition (Ho and Crabtree, 2010; Ronan et al., 2013).

Combinatorial assembly of BAF subunits can dramatically alterthe function of the complex with developmental specificity. Forexample, the twoBAFATPase subunits that compose nBAF (Brg1 andhBrm) share 75% sequence homology (Kadam and Emerson, 2003)and both types of BAF complexes possess nucleosome remodelingcapabilities (Wang et al., 1996b) similar to those first characterizedin the yeast SWI/SNF complex (Côté et al., 1994). However, nullmutations in the two proteins produce very different phenotypes.Homozygous deletions of Brg1 are embryonically lethal while micewith deletions of hBrm appear to develop normally (Bultman et al.,2000; Reyes et al., 1998). The phenotypic differences may be drivenby the inclusion of Brg1, but not hBrm, in BAF complexes foundexclusively in embryonic stem cells (Ho et al., 2009b). Why oneATPase is included preferentially over the other is potentially due tothe divergence in the N-terminal regions of Brg1 and hBrm thatallow interactions with different classes of transcription factors.Brg1 interactswith zincfingerproteinswhereashBrm interactswithcomponents of the Notch signaling pathway (Kadam and Emerson,

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

2003). Consequently, the selection of the ATPase subunit canpotentially drive interactions with different promoters duringcellular proliferation and differentiation and may result in uniqueremodeling functions (Kadam and Emerson, 2003).

Different subunit compositions may lead to differential regula-tion of specific target gene sets. The type of ARID (AT-rich Inter-active Domain) subunit present in the complex can alter thetranscriptional targets. For example, in HeLa cells BAF (containsBAF250A (ARID1A) or BAF250B (ARID1B)) and P-BAF (containsBAF200 and not BAF250A/B) complexes differentially regulateinterferon-responsive genes, a selectivity conferred by the BAF200subunit (Yan et al., 2005). Even though the alternate BAF subunitsBAF250A and BAF250B are expressed within the same cell types(not tissue or cell-type specific) (Wang et al., 2004), the two sub-units result in different BAF complexes with differential regulationof gene expression. The BAF250 subunits do not possess sequencespecific DNA binding domains (Dallas et al., 2000; Wang et al.,2004), indicating that they alter BAF complex function throughdifferences in proteineprotein interactions. BAF250A containingBAF complexes form repressive complexes with Sin3A and HDAC1/2 that represses cell cycle gene expression while BAF250B-containing BAF complexes interact with the histone acetyl-transferase Tip60 and HDAC3 that serves to activate some of thesame genes. By forming these two unique complexes the type ofBAF250 subunit can dictate the direction of cell cycle gene

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

Fig. 3. Mutations in BAF complexes Identified in Human Patients. Each colored “X”represents an identified mutation for the given human disorder (either by wholeexome sequencing or gene wide association studies). All mutations are shown in thecontext of the nBAF complex, but many of the mutant subunits are also shared withesBAF and npBAF.

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expression (Nagl et al., 2007). Work on the BAF200 and BAF250subunits highlight the impact of combinatorial assembly on regu-lating gene expression, where the substitution of a single subunitcan serve as a switch from a gene regulatory program of activationto repression. Future work will be needed to more completelydelineate how the unique subunit composition of BAF complexescontributes to coordinated regulation of gene expression. Anintriguing idea is that this combinatorial complexity may corre-spond with the spectrum of intellectual disability disordersobserved in humans.

4. Chromatin remodeling Complexesdcell type specificity

Different cell types also have specialized BAF complexes thatregulate unique sets of genes required for cell-specific functions.Currently there are several complex variants, each with uniquecombinations of subunits that confer either cell-type specificexpression or function: embryonic stem cell BAF (esBAF)(Ho et al.,2009a), neuronal progenitor BAF (npBAF) (Lessard et al., 2007), andneuronal BAF (nBAF) (Olave et al., 2002) (Fig. 2). Embryonic stemcells (ESCs) express esBAF that is defined by the inclusion of Brg1,BAF155 (homodimer), and BAF60A or B subunits and the absence ofBrm, BAF170, and BAF60C (Ho et al., 2009b) (Fig. 2). This uniquecomplex is required for ESC pluripotency and self-renewal throughinteractions with ESC unique transcription factors (Ho et al., 2009b,2009a; 2011). Genome-wide mapping found that Brg1 wasenriched specifically at genes that were uniquely down-regulatedin ESCs including developmental and lineage-determinant genes,indicating that esBAF plays a role in preventing premature differ-entiation. In contrast, Brg1 also repressed several genes uniquelyexpressed in ESCs indicating amore subtle role for esBAF in refiningthe ESC transcriptional network(Ho et al., 2009a; Kidder et al.,2009). Similarly, a P-BAF complex isolated from an ESC line differ-entially regulated transcription targets compared to the esBAFcontaining BAF250A (Kaeser et al., 2008). The findings in ESCsdemonstrate how a unique composition of BAF subunits (i.e. esBAF)directs gene expression profiles required for maintaining cellularidentity (i.e. ESC pluripotency).

During brain development the BAF complex undergoes a highlycoordinated exchange of subunits as ESCs differentiate intoneuronal precursors and then into mature, post-mitotic neurons.For the transition from esBAF to a neural stem/progenitor specificversion of the complex (npBAF) several specific subunits areexchanged. The npBAF complex is defined by the inclusion ofBAF170, decreased incorporation of BAF60b and the presence ofeither Brg1 (same as esBAF) or Brm (not present in esBAF) (Lessardet al., 2007; Staahl et al., 2013) (Fig. 2). Microarray analysis of E12.5mouse brains with deletion of Brg1 specifically in neural stem/progenitors cells suggests that the npBAF complex regulates stemcell self-renewal and/or maintenance by enhancing expression ofcomponents in the Notch signaling pathway while also repressingexpression of components and downstream targets of the SonicHedgehog pathway (Lessard et al., 2007). Manipulations thatdecrease npBAF function (i.e. knockdown of BAF45a, BAF53a(Lessard et al., 2007), or SS18 (Staahl et al., 2013) impair neuralstem/progenitor proliferation. Together these findings point to aunique role for npBAF in regulating gene expression required forneuronal progenitor proliferation (Fig. 3).

The transition (E13.5 in mice) from npBAF to the post mitoticneuron-specific nBAF requires the developmentally regulatedswitch in subunits from BAF45a to BAF45b/c, BAF53a to BAF53b(Lessard et al., 2007; Wu et al., 2007), and SS18 to CREST (Staahlet al., 2013). The nBAF complex contains at least 15 assembledsubunits, two of which are neuron specific (BAF53b and BAF45b).The exchange of BAF53a for BAF53b is regulated by the microRNAs

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miR-9* and miR-124 (Yoo et al., 2009). Prior to neuronal differen-tiation, miR-9* and miR-124 expression are repressed, allowingBAF53a expression and neuronal progenitor proliferation (ie.npBAF). When neural progenitors differentiate, miR-9* and miR-124 are expressed which in turn represses BAF53a and allowsexpression of BAF53b (Yoo et al., 2009). The highly orchestratedregulation of subunit exchange highlights the importance ofneuron-specific subunits in nBAF’s role in neuronal differentiation.

As one of the neuron-specific subunits of nBAF, BAF53b (alsoknown as hArpNalpha or Actl6b) seems to play a critical role innBAF function. BAF53b was first identified by its homology to thenon-neuronal isoform BAF53a (Actl6a) (Harata et al., 1999). BAF53awas first identified as an actin related protein (ARP) within the BAFcomplex in T lymphocytes (Zhao et al., 1998). BAF53a and b areencoded by two separate genes that share 93% similarity (Harataet al., 1999; Olave et al., 2002). Both proteins localize to the nu-cleus, specifically in regions enriched in euchromatin, but not inheterochromatin regions (Harata et al., 1999). While BAF53b isexpressed only in neurons and is found only within nBAF, BAF53a isfound within all human tissues except the nervous system and inseveral distinct CRCs other then BAF (Olave et al., 2002; Park et al.,2002).

The neuron-specific subunits of nBAF appear to confer a criticalrole for nBAF’s regulation of neuronal gene expression required fordendritic arborization, branching and synapse formation (Staahlet al., 2013; Wu et al., 2007). Mice lacking BAF53b die at two dayspostnatal. Neuronal cultures made from BAF53b knockout micehave severe deficits in synapse formation, activity-dependentdendritic outgrowth, and axonal myelination. The absence ofBAF53b does not disrupt formation of the nBAF complex, as theremaining subunits show normal assembly (Wu et al., 2007). Thedendritic phenotype depends on miR-9* and miR-124 binding sitesin the BAF53a 30UTR, indicating that the miR-mediated switch fromBAF53a to BAF53b is critical for nBAF’s function in neuronaldevelopment (Yoo et al., 2009). As predicted from these findings,disrupting the transition from npBAF to nBAF by over-expression ofBAF45a and BAF53a in the developing chicken neural tube blocksneuronal differentiation of specific classes of neurons (Lessardet al., 2007).

5. BAF53b: A key neuron-specific subunit of nBAF

As a dedicated member of nBAF, BAF53b plays a critical andunique role in neuronal branching and synapse formation. Therewas no rescue of lethality or dendritic phenotype by over expres-sion of BAF53a in Baf53b�/� knockout mice (Wu et al., 2007).BAF53a and BAF53b show the largest sequence divergence withinsubdomain2 (aa 39e82). Switching the subdomain2 region ofBAF53a for b restored dendritic outgrowth and rescued deficits in

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

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gene expression (see below) in Baf53b�/� knockout neuronal cul-tures. The reverse swap (BAF53b with subdomain2 from BAF53a)failed to rescue the phenotype, suggesting a critical role for sub-domain 2 of BAF53b (Wu et al., 2007). RNAi mediated knockdownof Brahma associated protein 55 (Bap55), a homolog of both BAF53aand b, reduces dendritic arborization and routing in Drosophila(Parrish et al., 2006). Similarly, BAP55 knockouts produce mis-targeting of olfactory projection neurons in vivo (Tea and Luo, 2011).The phenotype can be rescued by expression of BAP55, BAF53a, orBAF53b. The rescue of the dendritic phenotype by BAF53a may atfirst appear contradictory to BAF53b’s selective role in dendriticarborization in mammals. However, in Drosophila BAP55 hasapproximately equal homology to both BAF53a and b and is foundin additional CRCs outside of the BAF complex. These findingsindicate that BAF53b confers a unique function to the mammaliannBAF complex that cannot be replaced by the non-neuronalBAF53a, further highlighting the specialization of combinatorallyassembled and cell-type specific BAF complex function.

Even though targeting BAF53b may be one of the most directways of manipulating nBAF, siRNA knockdown of other nBAFcomponents (Brg1, Baf57 or Baf45b) in primary mouse neuronalcultures results in deficits in dendritic growth comparable toBAF53b knockout neuronal cultures (Wu et al., 2007). Similarly, inDrosophila deletion of other BAP (BAF complex homolog inDrosophila) components including Brm and Snr1 (Baf47) produceglobal mistargeting and abnormalities in cell morphology (Tea andLuo, 2011) and RNAi mediated knockdown of Brm, Bap60 (Baf60), orSnr1 alter dendritic routing and branching (Parrish et al., 2006). InCaenorhabditis elegans deletion of ham-3 (Baf60) disrupts theexpression of genes associated with serotonin synthesis andtransport within a specific subset of serotonergic neurons andproduces deficits in axon pathfinding (Weinberg et al., 2013). Thesefindings indicate that nBAF is a critical regulator of dendriticarborization and branching and that disruption of nBAF functionresults in abnormal dendritic maturation across multiple species.

In primary cortical neuron cultures, BAF53b coordinatesexpression of specific transcriptional profiles required for dendriticarborization and branching. For example, loss of BAF53b inneuronal cultures results in misregulation of several Rho familyGTPase regulators that are critically important for activity-dependent dendritic development. At least one of these RhoGTPases, Ephexin1, appears critical for BA53b mediated dendriticdevelopment. Baf53b�/� knockout cultures have reduced Exphexin1expression, BAF53b has been shown to bind to the Ephexin1 pro-moter, and over-expression of Ephexin1 rescued the dendriticphenotype in Baf53b�/� knockout cultures (Wu et al., 2007).Together these findings suggest a critical role for BAF53b and thenBAF complex in regulating a transcriptional profile required fornormal dendritic development.

How nBAF specifically targets and regulates neuronal genesrequired for dendritic maturation is unclear; however BAF53b ap-pears to play a critical role in targeting nBAF and the transcriptionfactor Calcium-responsive transactivator (CREST or SS18L1) tospecific promoter regions (Wu et al., 2007). CREST is activated bycalcium influx in response to neuronal depolarization (Aizawaet al., 2004), CREST and nBAF directly interact (Qiu and Ghosh,2008; Staahl et al., 2013; Wu et al., 2007) and CREST is nowconsidered a subunit of the nBAF complex (Staahl et al., 2013). Thisis a significant finding as the interaction between CREST and nBAFsubunits provides a potential link between nBAF-mediated nucle-osome remodeling and calcium-dependent neuronal activity.While BAF53b is not required for the CREST-nBAF interaction, lossof BAF53b disrupts localization of nBAF and CREST to target pro-moters and disrupts gene expression involved in dendriticoutgrowth (Wu et al., 2007). Similar to the dendritic branching and

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

arborization deficits observed in BAF53b knockout neuronal cul-tures, cultures from CREST knockout mice have severe deficits inactivity-dependent dendritic development (Aizawa et al., 2004; Qiuand Ghosh, 2008). Blocking the transition from SS18 (found innpBAF) to CREST (nBAF specific) during neuronal differentiation byover-expressing SS18 also impairs activity-dependent dendriticgrowth and branching (Staahl et al., 2013). These findings suggestBAF53b and CREST are key components of activity-dependentnucleosome remodeling required for dendritic spine dynamics.

There also appears to be a link between CREST function andhuman neurodegenerative disease. Recent exome sequencing inpatients with sporadic amyotrophic lateral sclerosis (ALS), aneurodegenerative disease characterized by motor neuron loss,identified a de novo truncation mutation in CREST. This truncationmutation specifically deleted the portion of CREST that interactswith CREB binding protein (CBP) (Aizawa et al., 2004; Qiu andGhosh, 2008), a histone acetyl transferase required for long-termmemory formation (for review see Barrett and Wood, 2008;Peixoto and Abel, 2013)). Over-expressing this truncated versionof CREST in primary cortical or motor neuron cultures impairedactivity-dependent dendritic outgrowth and branching. Similardeficits in dendritic development were found with over-expressionof CREST with a missense mutation identified in an ALS patientwith a known family history of ALS (Chesi et al., 2013). Togetherthese findings indicate a critical role for the nBAF component CRESTin dendritic development and human disease. Further work will beneeded to clarify the function of CREST in the adult nervous systemand how CREST mutations may be causally linked to sporadic ALSand other neurodegenerative diseases.

6. Chromatin remodeling complexes and disorders of humancognition

Recently, whole exome sequencing in human patients withseveral distinct types of intellectual disability disorders identifiedmutations in several BAF subunits. Tsurusaki et al. (2012) per-formed whole exome sequencing on five patients with Coffin-Sirissyndrome (CSS), a developmental disorder characterized bycognitive delay, microcephaly, abnormal facial features, and eitherhypoplasia or absence of the nail on the fifth digit of hands or feet(Coffin and Siris, 1970). Two of the five patients had de novo het-erozygous mutations in Baf47 (SMARCB1). The authors thenexamined 23 additional CSS patients by melting analysis for po-tential mutations in 15 of the various BAF subunits. In total, 20 ofthe 23 CSS individuals had a mutation in one of six BAF subunits(Brm, Brg1, Baf47, BAF250b, BAF250a, and Baf57) giving an overallmutation detection rate of 87% (Tsurusaki et al., 2012). Similarly, anindependent group found de novo truncation mutations in BAF250b(ARID1B) using exome sequencing of three CSS patients (Santenet al., 2012). Deletions and mutations that produce hap-loinsufficiency of BAF250b have been found in patients with intel-lectual disability disorder, corpus callosum abnormalities, speechimpairments, and autism (Backx et al., 2011; Halgren et al., 2011;Hoyer et al., 2012; Nord et al., 2011).

Recent human exome sequencing has also revealed a role for theBAF complex in Nicolaides-Baraitser syndrome (NBS), an intellec-tual disability disorder characterized by impaired language andattention span, seizures, sparse hair, short stature, abnormal facialfeatures,microcephaly, and severe intellectual disability (Nicolaidesand Baraitser, 1993; Sousa et al., 2009). In eight out of ten patientswith NBS whole exome sequencing identified de novomutations inBrm. Additional targeted sequencing of Brm in 34 additional NBSpatients identified 28 Brm mutations, none of which were presentin 1300 screened control samples. The majority of mutationsoccurred within conserved protein motifs including domains for

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DNA binding, acetylated lysine recognition (bromo), and ATP hy-drolysis (Van Houdt et al., 2012). In parallel, SNP arrays followed bytargeted sequencing of three NBS patients identified de novo het-erozygous mutations in the C-terminal helicase domain of Brm andwere predicted to disrupt ATPase function (Wolff et al., 2011).

In addition to intellectual disability disorders, mutations incomponents of the BAF complex have also been linked to autism.Whole exome sequencing of ASD patients and their parents iden-tified de novo single nucleotide variants in Baf155, Baf170, Baf180,and Baf250b in ASD individuals (Neale et al., 2012; O’Roak et al.,2012). Furthermore, when these data were combined with thosefrom two other recent exome sequencing studies (Iossifov et al.,2012; Sanders et al., 2012) (965 ASD individuals and a total of 121gene disrupting mutations), a higher proportion of disruptivemutations belonging to the ‘chromatin regulator’ gene ontologycategory was observed in ASD cases compared to controls, sup-porting the contribution of this category to ASD risk (Ben-Davidand Shifman, 2013).

The BAF complex has also been recently implicated in schizo-phrenia (SZ). Functional interactome models using genome-wideassociation studies (GWAS) found an interacting network be-tween Brm and eight other GWAS identified genes involved inschizophrenia (Loe-Mie et al., 2010). In a Japanese population fourdifferent single nucleotide polymorphisms (SNPs) in Brm werefound to associatewith schizophrenia (Koga et al., 2009). Two of theintronic SNPS (intron 12 and 19) that were foundmore frequently inschizophrenics were correlatedwith lower overall expression levelsof Brm in the postmortem human prefrontal cortex. A SNP identi-fied in exon 33 of Brm of schizophrenic patients alters the aminoacid sequence at position 1546 from aspartic acid (D) to glutamicacid (E).When over-expressed in cell culture the E risk allele alteredcell morphology and produced a partial mislocalization of Brm outof the nucleus, indicating a decrement in Brm and BAF function.This was further supported by an examination of gene expressionfollowing transfections with either E or D variants compared tosiRNA targeted to Brm. Expression changes with siRNA to Brmweresimilar to those with the E variant further supporting a loss of Brmfunction for the E variant (Koga et al., 2009). Furthermore, geneexpression changes following siRNA knockdown of Brm correlatedwith expression observed in prefrontal cortex from Brm knockoutmice and postmortem prefrontal cortex of schizophrenics. Brmknockout mice are viable and develop normally (see above) buthave impaired social interactions in that they spend less timeexploring a novel intruder mouse even though they have normalnovelty seeking behavior (Koga et al., 2009). The impairment insocial interaction is particularly interesting given that social inter-action problems are also one of the key hallmarks in ASD. It appearsthat Brm may also be a viable therapeutic target for SZ given thatantisychotic drug treatment (4 wks haloperidol or olanzapine)increased Brm expression (Koga et al., 2009).

One of the key hallmarks found in postmortem brains frompatients with SZ or ASD is alterations in dendritic spine density.Layer 3 pyramidal neurons in prefrontal and temporal cortex fromSZ patients have a marked decrease in spine density compared tonon-SZ controls (Garey et al., 1998; Glantz and Lewis, 2000).Conversely, spines on apical dendrites of pyramidal cells in layer 2of frontal, temporal and parietal cortex and layer 5 of temporalcortex show a higher density in ASD patients compared to matchedcontrols. The density of spines was also inversely related to IQ(Hutsler and Zhang, 2010). GWAS and whole exome sequencing inhumans have identified mutations in various BAF subunits in hu-man disorders including CCS, NBS, ASD, and SZ, indicating a criticalrole for the loss of transcriptional regulation in the etiology of thesedisorders. It is tempting to speculate that BAF may control a tran-scriptional network required for dendritic development in humans

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

and that mutations altering BAF function consequently producesdendritic abnormalities characteristic of these disorders. In supportof this hypothesis, BAF53b plays a key role in dendritic arborizationand spine formation in vitro (Tea and Luo, 2011; Wu et al., 2007).SiRNA knockdown of Brm in primary mouse cortical cultures in-creases spine number, specifically due to an increase in mushroomspines (Loe-Mie et al., 2010). A shift towards increased mushroomtype spines is also observed in vivo with a dominant negativeBAF53b transgene over-expression (Vogel-Ciernia et al., 2013). Micewith heterozygous knockout of BAF53b have altered gene expres-sion profiles including genes involved in actin cytoskeletalremodeling and the post synaptic density (discussed below)(Vogel-Ciernia et al., 2013). The findings on nBAF’s regulation of geneexpression involved in synaptic function both during development(Chesi et al., 2013; Staahl et al., 2013; Tea and Luo, 2011; Wu et al.,2007) and in the adult (Vogel-Ciernia et al., 2013) are consistentwith the dendritic spine abnormalities observed in humans with SZand ASD. However, future workwill be needed to elucidate how thespecific mutations found in various human cognitive disordersimpact nBAF structure (physical subunit composition) and activity,as well as the precise role of different subunits of various CRCs inspecific cellular functions.

7. Neuron-specific chromatin remodeling in long-termmemory formation

While BAF53b’s unique contribution to nBAF’s role in dendriticdevelopment in vitro was becoming apparent, how the impairedfunction of nBAF leads to adult cognitive impairments was un-known. In order to address this question Vogel-Ciernia et al. (2013)targeted the neuron-specific nBAF subunit BAF53b to examine therole of nBAF in long-term memory, long-term potentiation (a formof synaptic plasticity), and gene expression. The unusual dedicationof BAF53b to a single neuronal complex makes it an ideal target forgenetic manipulations designed at elucidating the role of the nBAFcomplex in neuronal function. The authors used both traditionalBAF53b heterozygous knockout mice and transgenic mice over-expressing a dominant negative form of BAF53b (deletion of a hy-drophobic domain predicted to mediate proteineprotein in-teractions (Park et al., 2002)) under the CamKIIa promoter (restrictsexpression to forebrain excitatory neurons and postnatal develop-ment (Kojima et al., 1997; Mayford et al., 1996)). Both the dominantnegative and heterozygous knockouts showed severe long-termmemory deficits, but normal short-term memory. Importantly,the normal short-term memory performance indicates that thegenetically altered animals were able to perform the task (ie.normal exploration, attention, etc) and that the memory deficits atthe long-term time point were due to a failure of memoryconsolidation.

To further assess the role of BAF53b in the adult brain comparedto its role in development, Vogel-Ciernia et al. (2013) performed arescue experiment in the BAF53b heterozygous knockout mice byinjecting an adeno-associated virus expressing wildtype BAF53b inthe dorsal hippocampus of adult animals. Hippocampal expressionof wildtype BAF53b in the BAF53b heterozygous knockouts rescuedthe long-term object location memory (hippocampal dependent)deficits indicating that BAF53b is required for long-term memoryformation in the adult animal independent of its role in develop-ment. In the same animals the hippocampal BAF53b reintroductionfailed to rescue (as predicted) the hippocampal independent objectrecognition task, further implicating a specific role for BAF53b inmemory formation and not an alteration in brain state orprocessing.

In parallel to the observed deficits in long-term memory, theBAF53b mutant mice also showed deficits in the maintenance of

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long-term potentiation (LTP), an electrophysiological correlate oflong-term memory. In acute hippocampal slices theta burse stim-ulation (TBS) was used to induce robust potentiation in slices fromBAF53b heterozygous knockout animals, the dominant negativeBAF53b transgenics, and wildtype littermate controls. The hetero-zygous knockout animals and the lower expressing dominantnegative mice both showed a normal LTP induction (short-termpotentiation) and a failure to stably maintain the potentiation witha decay back to baseline. The highly expressing dominant negativeline had an increase in the initial potentiation followed by a lack ofLTP maintenance similar to the other lines. The increase in short-term potentiation in the high expressing dominant negative ap-pears to be due depressed axon excitability and increased neuro-transmitter mobilization. All other measures of baseline physiologyincluding response to the TBS were normal in these animals as wellas the other BAF53b mutant lines. Overall, it is evident that BAF53bis necessary for stabilizing long-lasting forms of potentiation,correlating with observed long-term memory impairments.

In support of the deficits in synaptic plasticity observed withperturbations to BAF53b, the BAF53b heterozygous knockouts havedeficits in synaptic signaling following TBS. Specifically, BAF53bheterozygous knockout mice lack the induction of phosphorylatedcofilin (p-cofilin), with no change in PSD95 expression, followingTBS that is observed in slices from wildtype animals. This deficitindicates a breakdown in the signaling cascade leading to actincytoskeleton remodeling and may underlie the deficits in LTP inthese animals (Lynch et al., 2013). In addition, the high expressingdominant negative animals show an alteration in dendritic spinemorphology at three weeks of age. The BAF53bmutantmice showadecrease in thin and an increase in mushroom spines on both themain stem and oblique apical branches of hippocampal CA1 pyra-midal neurons. It is currently unknown if these spine alterationsmaintain into adulthood and whether or not they contribute to thedeficits in memory or synaptic plasticity observed in these mice.

The specific deficits in long-term memory and maintenance ofLTP indicate a transcription dependent mechanism for BAF53bfunction. To assess a role for BAF53b in regulating transcriptionfollowing a learning event, Vogel-Ciernia et al. (2013) conducted anRNA Sequencing experiment to assess gene expression in dorsalhippocampus from wildtype and BAF53b heterozygous knockoutmice sacrificed either from the homecage (baseline) or 30 minfollowing object location training. The resulting gene expressionprofiles indicated that the majority of genes were not differentiallyregulated at baseline. There were a group of genes that increased inexpression in both genotypes following training and interestinglythis group contained almost all of the identified immediate earlygenes (IEGs). The normal induction of IEGs in the BAF53b hetero-zygous knockout mice indicates that the long-term memory im-pairments observed in these animals are not due to misregulationof IEG expression but to a different mechanism. There were genesincreased following training in the wildtype animals that failed toincrease in the BAF53b mutant mice, as well as genes that did notturn on in the wildtype following training that aberrantly activatedin the BAF53b heterozygous knockouts. These misregulated geneswere enriched for gene ontology terms involving regulation oftranscription, neurogenesis, and higher order chromatin structure.Within the misregulated gene profiles were several targets relatedto the actin cytoskeleton and post synaptic density (PSD) that couldpotentially link the deficits in transcription to the deficits in p-cofilin induction and synaptic plasticity. These genes includedmiroRNAs and members of the Rac-PAK and RhoA-LIMK pathways,all critical components of activity-dependent cytoskeletal remod-eling machinery in the PSD (Boda, et al., 2010; Impey et al., 2010;Rex et al., 2009). Together the RNA-Seq and synaptic signaling (p-cofilin) results indicate a role for nBAF in regulating gene

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

expression required for synaptic structure and function and thatthe failure of these mechanisms in the BAF53b mutant mice mayunderlie their deficits in synaptic plasticity and long-termmemory.

8. Conclusion

The BAF complex appears to play a key role in normal humanbrain development such that even heterozygous mutations thatproduce haploinsufficiency can lead to severe intellectual disabilityand developmental abnormality. Any disruption to the BAF com-plex appears to disrupt function since mutations in different BAFsubunits can lead to similar phenotypes (intellectual impairments).To date all identified BAF mutations associated with intellectualdisability disorders, ASD, and SZ have been to subunits commonlyshared among P-BAF, esBAF, npBAF, and nBAF. Given that each ofthese complexes regulates unique gene expression profiles, it iscurrently unclear how mutations in the various BAF complexesalter either cell-type or developmental stage specific gene expres-sion that ultimately contributes to human disorders.

The finding that nBAF plays a critical role in adult long-lastingforms of synaptic plasticity and memory (Vogel-Ciernia et al.,2013) provided the first evidence that nBAF may be playing a rolebeyond early brain development in human intellectual disabilitydisorders. The deficits in synaptic plasticity (LTP maintenance andp-cofilin levels) and expression of genes found in both the PSD andcytosketetal remodeling machinery indicate a potential role forBAF53b and the nBAF complex in regulating dendritic spine for-mation and plasticity. The misregulation of genes required forproper activation of activity-dependent cytoskeletal remodeling isreminiscent of recent findings of perturbations of the cytoskeletalmachinery in individuals with ASD. For example, deletions in genesinvolved in GTPases/Ras signaling and specifically the Rho GTPasesare more common in individuals with ASD than controls (Pintoet al., 2010), and network level analysis of rare de novo CNVsfound in ASD individuals (but not controls) suggests a role for genesfound in the PSD that are linked with spine formation and plasticityin ASD (Gilman et al., 2011). These findings are consistent with thehypothesis that a critical component of the pathology of both ASDand SZ is alterations of dendritic spines (Penzes et al., 2011).However, there is increasing evidence for the role of transcriptionregulation, via nucleosome remodeling, in ASD (Ben-David andShifman, 2013) potentially as an upstream regulator of coordinategene expression required for the expression of synaptic and cyto-skeleton associated genes. If nBAF regulates some of these samegenes in humans as in mice, restoring or augmenting nBAF functioncould serve as a powerful method for therapeutically targeting aspecific set of misregulated target genes.

In order to more fully understand the role of nBAF in neuronalfunction further work is needed to characterize how CRCs actin vivo to alter chromatin structure and regulate gene expression. Todate most of the information regarding mechanisms of CRC func-tion comes from artificially assembled arrays that lack the sec-ondary and tertiary structure of chromatin that is observed in vivoand often utilize only a single promoter or defined DNA regulatorydomain. There is growing evidence that CRCs may mediate sec-ondary or even higher order chromatin structure. Even on artifi-cially assembled polynucleosome arrays, a single yeast SWI/SNFcomplex can interact withmultiple DNA/nucleosome sites resultingin the formation of DNA loops (Bazett-Jones et al., 1999) (see Fig. 1).Brg1 has been shown to be required for cell-type specific chro-mosomal loop formation between unique up-stream regulatoryelements and the beta-globin (Kim et al., 2009b) and alpha-globinpromoters (Kim et al., 2009a). Thus, one exciting possibility is thatnucleosome remodeling via CRCs provides the chromosomal

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flexibility to allow chromosomal looping for coordinate generegulation.

Recent high throughput genomic studies (RNA-Seq, ChIP-Seq,Mnase-Seq, Hi-C, etc.) will be needed to delineate the role ofCRCs in regulating chromatin structure on a larger scale and acrossmultiple gene targets. For example, Mnase-Seq (microccocalnuclease digestion followed by high throughput sequencing toextract nucleosome positions across the genome) experimentswere recently used to examine the impact of knocking out eitherBrg1 or BAF47 (Snf5) on nucleosome positioning in murine em-bryonic fibroblasts. Loss of either subunit resulted in disruption ofnucleosome occupancy and altered nucleosome phasing aroundthe transcription start site of a large number of promoters(Tolstorukov et al., 2013). Similarly, Brg1 knockdown with shRNAalters nucleosome positioning at specific enhancer elements indi-cating that BAF complexes may act to shift flanking nucleosomesaway from these sites to allow access to the underlying DNA duringcellular differentiation (Hu et al., 2011). In addition, Hi-C methods(chromatin conformation capture followed by next generationsequencing) have also been recently used to characterize the globalthree-dimensional genome organization of several cell lines andthe mouse cortex and revealed large chromatin interaction do-mains that were conserved across cell types (Dixon et al., 2012). Itwill become increasingly important to understand how nBAF, andBAF53b, mediates nucleosome remodeling necessary for chromo-somal looping mechanisms that direct coordinate gene expressionfor specific cell function.

Considering that the nBAF complex is required for dendriticdevelopment (Chesi et al., 2013; Staahl et al., 2013; Tea and Luo,2011; Wu et al., 2007) as well as synaptic plasticity and memoryin the adult (Vogel-Ciernia, et al., 2013), it is not surprising thatmutations in components of the BAF complex in humans are foundin multiple cognitive disorders (ASD, ID, and SZ) as well as theneurodegenerative disorder ALS. Future work will be needed tofurther characterize the role for BAF complexes in the etiology ofthese disorders and to clarify the transcriptional networks theyregulate. However, given that both the developmental phenotype(Tea and Luo, 2011; Wu et al., 2007) and adult memory deficits(Vogel-Ciernia et al., 2013) were reversible upon reintroduction ofBAF53b, targeting specific BAF subunits may prove a valuabletherapeutic option for the future treatment of human cognitivedisorders.

Acknowledgments

This work was funded by NIMH and NIDA grants (MH081004,MH101491, DA025922, DA 036984) to M.A. Wood and NIMH (F31-MH098565) to A.V.C.

References

Aizawa, H., Hu, S.-C., Bobb, K., Balakrishnan, K., Ince, G., Gurevich, I., Cowan, M.,Ghosh, A., 2004. Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303, 197e202.

Alberini, C.M., 2009. Transcription factors in long-term memory and synapticplasticity. Physiol. Rev. 89 (1), 121e145.

Backx, L., Seuntjens, E., Devriendt, K., Vermeesch, J., Van Esch, H., 2011. A balancedtranslocation t(6;14)(q25.3;q13.2) leading to reciprocal fusion transcripts in apatient with intellectual disability and agenesis of corpus callosum. Cytogenet.Genome Res. 132, 135e143.

Baker-Andresen, D., Ratnu, V.S., Bredy, T.W., 2013. Dynamic DNA methylation: aprime candidate for genomic metaplasticity and behavioral adaptation. TrendsNeurosci. 36, 3e13.

Bali, P., Kenny, P.J., 2013. MicroRNAs and drug addiction. Front. Genet. 4.Bannister, A.J., Kouzarides, T., 2011. Regulation of Chromatin by Histone Modifica-

tions, vol. 21. Nature Publishing Group, pp. 381e395.Barrett, R.M., Wood, M.A., 2008. Beyond transcription factors: the role of chromatin

modifying enzymes in regulating transcription required for memory. Learn.Mem. 15, 460e467.

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

Bazett-Jones,D.P., Côté, J., Landel, C.C., Peterson, C.L.,Workman, J.L.,1999. TheSWI/SNFcomplexcreates loopdomains inDNAandpolynucleosomearrays andcandisruptDNA-histone contacts within these domains. Mol. Cell. Biol. 19, 1470e1478.

Ben-David, E., Shifman, S., 2013. Combined analysis of exome sequencing pointstoward a major role for transcription regulation during brain development inautism. Mol. Psychiatry 18 (10), 1054e1056.

Boda, B., Dubos, A., Muller, D., 2010. Signaling mechanisms regulating synapseformation and function in mental retardation. Curr. Opin. Neurobiol. 20 (4),519e527.

Bredy, T.W., Lin, Q., Wei, W., Baker-Andresen, D., Mattick, J.S., 2011. MicroRNA regu-lation of neural plasticity and memory. Neurobiol. Learn. Mem. 96 (1), 89e94.

Bultman, S., Gebuhr, T., Yee, D., La Mantia, C., Nicholson, J., Gilliam, A., Randazzo, F.,Metzger, D., Chambon, P., Crabtree, G., Magnuson, T., 2000. A Brg1 null mutationin the mouse reveals functional differences among mammalian SWI/SNFcomplexes. Mol. Cell 6, 1287e1295.

Chesi, A., Staahl, B.T., Jovi�ci�c, A., Couthouis, J., Fasolino, M., Raphael, A.R.,Yamazaki, T., Elias, L., Polak, M., Kelly, C., Williams, K.L., Fifita, J.A.,Maragakis, N.J., Nicholson, G.A., King, O.D., Reed, R., Crabtree, G.R., Blair, I.P.,Glass, J.D., Gitler, A.D., 2013. Exome sequencing to identify de novo mutations insporadic ALS trios. Nat. Neurosci. 16, 851e855.

Clapier, C.R., Cairns, B.R., 2009. The biology of chromatin remodeling complexes.Annu. Rev. Biochem. 78, 273e304.

Coffin, G.S., Siris, E., 1970. Mental retardation with absent fifth fingernail and ter-minal phalanx. Am. J. Dis. Child 119, 433e439.

Cohen-Armon, M., Visochek, L., Katzoff, A., Levitan, D., Susswein, A.J., Klein, R.,Valbrun, M., Schwartz, J.H., 2004. Long-term memory requires polyADP-ribo-sylation. Sci. Signal. 304, 1820.

Côté, J., Quinn, J., Workman, J.L., Peterson, C.L., 1994. Stimulation of GAL4 derivativebinding to nucleosomal DNA by the yeast SWI/SNF complex. Science 265, 53e60.

Dallas, P.B., Pacchione, S., Wilsker, D., Bowrin, V., Kobayashi, R., Moran, E., 2000. Thehuman SWI-SNF complex protein p270 is an ARID family member with non-sequence-specific DNA binding activity. Mol. Cell Biol. 20, 3137.

Day, J.J., Sweatt, J.D., 2011. Epigenetic mechanisms in cognition. Neuron 70, 813e829.

Dixon, J.R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J.S., Ren, B., 2012.Topological domains in mammalian genomes identified by analysis of chro-matin interactions. Nature 485, 376e380.

Garey, L.J., Ong, W.Y., Patel, T.S., Kanani, M., Davis, A., Mortimer, A.M., Barnes, T.R.E.,Hirsch, S.R., 1998. Reduced dendritic spine density on cerebral cortical pyra-midal neurons in schizophrenia. J. Neurol. 65, 446e453.

Gilman, S.R., Iossifov, I., Levy, D., Ronemus, M., Wigler, M., Vitkup, D., 2011. Rare denovo variants associated with autism implicate a large functional network ofgenes involved in formation and function of synapses. Neuron 70, 898e907.

Glantz, L.A., Lewis, D.A., 2000. Decreased dendritic spine density on prefrontalcortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65e73.

Goldberg, S., Visochek, L., Giladi, E., Gozes, I., Cohen-Armon, M., 2009. PolyADP-ribosylation is required for long-term memory formation in mammals.J. Neurochem. 111, 72e79.

Gräff, J., Tsai, L.-H., 2013. Histone acetylation: molecular mnemonics on the chro-matin. Nat. Rev. Neurosci. 14, 97e111.

Halgren, C., Kjaergaard, S., Bak, M., Hansen, C., El Schich, Z., Anderson, C.M.,Henriksen, K.F., Hjalgrim, H., Kirchhoff, M., Bijlsma, E.K., 2011. Corpus callosumabnormalities, intellectual disability, speech impairment, and autism in patientswith haploinsufficiency of ARID1B. Clin. Genet. 82 (3), 248e255.

Harata, M., Mochizuki, R., Mizuno, S., 1999. Two isoforms of a human actin-relatedprotein show nuclear localization and mutually selective expression betweenbrain and other tissues. Biosci. Biotechnol. Biochem. 63, 917e923.

Hargreaves, D.C., Crabtree, G.R., 2011. ATP-dependent Chromatin Remodeling: Ge-netics, Genomics and Mechanisms. Nature Publishing Group, pp. 1e25.

Ho, L., Crabtree, G.R., 2010. Chromatin remodelling during development. Nature463, 474e484.

Ho, L., Jothi, R., Ronan, J.L., Cui, K., Zhao, K., Crabtree, G.R., 2009a. An embryonicstem cell chromatin remodeling complex, esBAF, is an essential component ofthe core pluripotency transcriptional network. Proc. Natl. Acad. Sci. U. S. A. 106,5187e5191.

Ho, L., Miller, E.L., Ronan, J.L., Ho, W.Q., Jothi, R., Crabtree, G.R., 2011. esBAF facilitatespluripotency by conditioning the genome for LIF/STAT3 signalling and byregulating polycomb function. Nat. Cell Biol. 13, 903e913.

Ho, L., Ronan, J.L., Wu, J., Staahl, B.T., Chen, L., Kuo, A., Lessard, J., Nesvizhskii, A.I.,Ranish, J., Crabtree, G.R., 2009b. An embryonic stem cell chromatin remodelingcomplex, esBAF, is essential for embryonic stem cell self-renewal and plurip-otency. Proc. Natl. Acad. Sci. U. S. A. 106, 5181e5186.

Hoyer, J., Ekici, A.B., Endele, S., Popp, B., Zweier, C., 2012. Haploinsufficiency ofARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is afrequent cause of intellectual disability. Am. J. Hum. Genet. 90, 565e572.

Hu, G., Schones, D.E., Cui, K., Ybarra, R., Northrup, D., Tang, Q., Gattinoni, L.,Restifo, N.P., Huang, S., Zhao, K., 2011. Regulation of nucleosome landscape andtranscription factor targeting at tissue-specific enhancers by BRG1. Genome Res.21, 1650e1658.

Hutsler, J.J., Zhang, H., 2010. Increased dendritic spine densities on cortical pro-jection neurons in autism spectrum disorders. Brain Res. 1309, 83e94.

Impey, S., Davare, M., Lesiak, A., Lasiek, A., Fortin, D., Ando, H., Varlamova, O.,Obrietan, K., Soderling, T.R., Goodman, R.H., Wayman, G.A., 2010. An activity-induced microRNA controls dendritic spine formation by regulating Rac1-PAKsignaling. Mol. Cell Neurosci. 43, 146e156.

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

A. Vogel-Ciernia, M.A. Wood / Neuropharmacology xxx (2013) 1e10 9

Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B.,Lee, Y.-H., Narzisi, G., Leotta, A., Kendall, J., Grabowska, E., Ma, B., Marks, S.,Rodgers, L., Stepansky, A., Troge, J., Andrews, P., Bekritsky, M., Pradhan, K.,Ghiban, E., Kramer, M., Parla, J., Demeter, R., Fulton, L.L., Fulton, R.S.,Magrini, V.J., Ye, K., Darnell, J.C., Darnell, R.B., Mardis, E.R., Wilson, R.K.,Schatz, M.C., McCombie, W.R., Wigler, M., 2012. De novo gene disruptions inchildren on the autistic spectrum. Neuron 74, 285e299.

Jiang, Y., Jakovcevski, M., Bharadwaj, R., Connor, C., Schroeder, F.A., Lin, C.L.,Straubhaar, J., Martin, G., Akbarian, S., 2010. Setdb1 histone methyltransferaseregulates mood-related behaviors and expression of the NMDA receptor sub-unit NR2B. J. Neurosci. 30, 7152e7167.

Jin, C., Zang, C., Wei, G., Cui, K., Peng, W., Zhao, K., Felsenfeld, G., 2009. H3.3/H2A.Zdouble variantecontaining nucleosomes mark “nucleosome-free regions” ofactive promoters and other regulatory regions. Nat. Genet. 41, 941e945.

Kadam, S., Emerson, B.M., 2003. Transcriptional specificity of human SWI/SNF BRG1and BRM chromatin remodeling complexes. Mol. Cell 11, 377e389.

Kadoch, C., Hargreaves, D.C., Hodges, C., Elias, L., Ho, L., Ranish, J., Crabtree, G.R.,2013. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexesidentifies extensive roles in human malignancy. Nat. Genet. 45 (6), 592e601.

Kaeser, M.D., Aslanian, A., Dong, M.-Q., Yates, J.R., Emerson, B.M., 2008. BRD7, anovel PBAF-specific SWI/SNF subunit, is required for target gene activation andrepression in embryonic stem cells. J. Biol. Chem. 283, 32254e32263.

Khavari, P.A., Peterson, C.L., Tamkun, J.W., Mendel, D.B., Crabtree, G.R., 1993. BRG1contains a conserved domain of the SWI2/SNF2 family necessary for normalmitotic growth and transcription. Nature 366, 170e174.

Kidder, B.L., Palmer, S., Knott, J.G., 2009. SWI/SNF-Brg1 regulates self-renewal andoccupies core pluripotency-related genes in embryonic stem cells. Stem Cells27, 317e328.

Kim, S.-I., Bresnick, E.H., Bultman, S.J., 2009a. BRG1 directly regulates nucleosomestructure and chromatin looping of the alpha globin locus to activate tran-scription. Nucleic Acids Res. 37, 6019e6027.

Kim, S.-I., Bultman, S.J., Kiefer, C.M., Dean, A., Bresnick, E.H., 2009b. BRG1 require-ment for long-range interaction of a locus control region with a downstreampromoter. Proc. Natl. Acad. Sci. U. S. A. 106, 2259e2264.

Koga, M., Ishiguro, H., Yazaki, S., Horiuchi, Y., Arai, M., Niizato, K., Iritani, S.,Itokawa, M., Inada, T., Iwata, N., Ozaki, N., Ujike, H., Kunugi, H., Sasaki, T.,Takahashi, M., Watanabe, Y., Someya, T., Kakita, A., Takahashi, H., Nawa, H.,Muchardt, C., Yaniv, M., Arinami, T., 2009. Involvement of SMARCA2/BRM in theSWI/SNF Chromatin-remodeling Complex in Schizophrenia, vol. 18(13),pp. 2483e2494.

Kojima, N., Wang, J., Mansuy, I.M., Grant, S.G., Mayford, M., Kandel, E.R., 1997.Rescuing impairment of long-term potentiation in fyn-deficient mice byintroducing Fyn transgene. Proc. Natl. Acad. Sci. U. S. A. 94, 4761e4765.

Kouzarides, T., 2007. Chromatin modifications and their function. Cell 128, 693e705.Kwon, H., Imbalzano, A.N., Khavari, P.A., Kingston, R.E., Green, M.R., 1994. Nucleo-

some disruption and enhancement of activator binding by a human SW1/SNFcomplex. Nature 370, 477e481.

Landry, C.D., Kandel, E.R., Rajasethupathy, P., 2013. New mechanisms in memorystorage: piRNAs and epigenetics. Trends Neurosci. 36 (9), 535e542.

Lemon, B., Inouye, C., King, D.S., Tjian, R., 2001. Selectivity of chromatin-remodellingcofactors for ligand-activated transcription. Nature 414, 924e928.

Lessard, J., Wu, J.I., Ranish, J.A., Wan, M., Winslow, M.M., Staahl, B.T., Wu, H.,Aebersold, R., Graef, I.A., Crabtree, G.R., 2007. An essential switch in subunitcomposition of a chromatin remodeling complex during neural development.Neuron 55, 201e215.

Levenson, J.M., Roth, T.L., Lubin, F.D., Miller, C.A., Huang, I.-C., Desai, P., Malone, L.M.,Sweatt, J.D., 2006. Evidence that DNA (cytosine-5) methyltransferase regulatessynaptic plasticity in the hippocampus. J. Biol. Chem. 281, 15763e15773.

Loe-Mie, Y., Lepagnol-Bestel, A.-M., Maussion, G., Doron-Faigenboim, A.,Imbeaud, S., Delacroix, H., Aggerbeck, L., Pupko, T., Gorwood, P., Simonneau, M.,Moalic, J.-M., 2010. SMARCA2 and other genome-wide supportedschizophrenia-associated genes: regulation by REST/NRSF, network organiza-tion and primate-specific evolution. Hum. Mol. Genet. 19, 2841e2857.

Lubin, F.D., Roth, T.L., Sweatt, J.D., 2008. Epigenetic regulation of BDNF gene tran-scription in the consolidation of fear memory. J. Neurosci. 28 (42), 10576e10586.

Lynch, G., Kramár, E.A., Babayan, A.H., Rumbaugh, G., Gall, C.M., 2013. Differencesbetween synaptic plasticity thresholds result in new timing rules for maxi-mizing long-term potentiation. Neuropharmacology 64, 27e36.

Mayford, M., Bach, M.E., Huang, Y.Y., Wang, L., Hawkins, R.D., Kandel, E.R., 1996.Control of memory formation through regulated expression of a CaMKIItransgene. Science 274, 1678e1683.

Middeljans, E., Wan, X., Jansen, P.W., Sharma, V., Stunnenberg, H.G., Logie, C., 2012.SS18 together with animal-specific factors defines human BAF-type SWI/SNFcomplexes. PLoS ONE 7, e33834.

Miller, C.A., Gavin, C.F., White, J.A., Parrish, R.R., Honasoge, A., Yancey, C.R.,Rivera, I.M., Rubio, M.D., Rumbaugh, G., Sweatt, J.D., 2010. Cortical DNAmethylation maintains remote memory. Nat. Neurosci. 13, 664e666.

Miller, C.A., Sweatt, J.D., 2007. Covalent modification of DNA regulates memoryformation. Neuron 53, 857e869.

Muchardt, C., Yaniv, M., 1993. A human homologue of Saccharomyces cerevisiaeSNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation bythe glucocorticoid receptor. EMBO J. 12, 4279e4290.

Nagl, N.G., Wang, X., Patsialou, A., van Scoy, M., Moran, E., 2007. Distinctmammalian SWI/SNF chromatin remodeling complexes with opposing roles incell-cycle control. EMBO J. 26, 752e763.

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

Neale, B.M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K.E., Sabo, A., Lin, C.-F., Stevens, C.,Wang, L.-S., Makarov, V., Polak, P., Yoon, S., Maguire, J., Crawford, E.L.,Campbell, N.G., Geller, E.T., Valladares, O., Schafer, C., Liu, H., Zhao, T., Cai, G.,Lihm, J., Dannenfelser, R., Jabado, O., Peralta, Z., Nagaswamy, U., Muzny, D.,Reid, J.G., Newsham, I., Wu, Y., Lewis, L., Han, Y., Voight, B.F., Lim, E., Rossin, E.,Kirby, A., Flannick, J., Fromer, M., Shakir, K., Fennell, T., Garimella, K., Banks, E.,Poplin, R., Gabriel, S., DePristo, M., Wimbish, J.R., Boone, B.E., Levy, S.E.,Betancur, C., Sunyaev, S., Boerwinkle, E., Buxbaum, J.D., Cook, E.H., Devlin, B.,Gibbs, R.A., Roeder, K., Schellenberg, G.D., Sutcliffe, J.S., Daly, M.J., 2012. Patternsand rates of exonic de novo mutations in autism spectrum disorders. Nature485, 242e245.

Nicolaides, P., Baraitser, M., 1993. An unusual syndrome with mental retardationand sparse hair. Clin. Dysmorphol. 2, 232e236.

Nord, A.S., Roeb, W., Dickel, D.E., Walsh, T., Kusenda, M., O’Connor, K.L., Malhotra, D.,McCarthy, S.E., Stray, S.M., Taylor, S.M., Sebat, J., King, B., King, M.-C.,McClellan, J.M., 2011. Reduced transcript expression of genes affected byinherited and de novo CNVs in autism. Eur. J. Hum. Genet. 19, 727e731.

O’Roak, B.J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B.P., Levy, R., Ko, A.,Lee, C., Smith, J.D., Turner, E.H., Stanaway, I.B., Vernot, B., Malig, M., Baker, C.,Reilly, B., Akey, J.M., Borenstein, E., Rieder, M.J., Nickerson, D.A., Bernier, R.,Shendure, J., Eichler, E.E., 2012. Sporadic autism exomes reveal a highly inter-connected protein network of de novo mutations. Nature 485, 246e250.

Olave, I., Wang, W., Xue, Y., Kuo, A., Crabtree, G.R., 2002. Identification of a poly-morphic, neuron-specific chromatin remodeling complex. Genes Dev. 16,2509e2517.

Park, J., Wood, M.A., Cole, M.D., 2002. BAF53 forms distinct nuclear complexes andfunctions as a critical c-Myc-interacting nuclear cofactor for oncogenic trans-formation. Mol. Cell. Biol. 22, 1307e1316.

Parrish, J.Z., Kim, M.D., Jan, L.Y., Jan, Y.N., 2006. Genome-wide analyses identifytranscription factors required for proper morphogenesis of Drosophila sensoryneuron dendrites. Genes Dev. 20, 820e835.

Peixoto, L., Abel, T., 2013. The role of histone acetylation in memory formation andcognitive impairments. Neuropsychopharmacology 38, 62e76.

Penzes, P., Cahill, M.E., Jones, K.A., VanLeeuwen, J.-E., Woolfrey, K.M., 2011. Dendriticspine pathology in neuropsychiatric disorders. Nat. Neurosci. 14, 285e293.

Pinto, D., Pagnamenta, A.T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J.,Magalhaes, T.R., Correia, C., Abrahams, B.S., Almeida, J., Bacchelli, E., Bader, G.D.,Bailey, A.J., Baird, G., Battaglia, A., Berney, T., Bolshakova, N., Bölte, S., Bolton, P.F.,Bourgeron, T., Brennan, S., Brian, J., Bryson, S.E., Carson, A.R., Casallo, G., Casey, J.,Chung, B.H.Y., Cochrane, L., Corsello, C., Crawford, E.L., Crossett, A.,Cytrynbaum, C., Dawson, G., de Jonge, M., Delorme, R., Drmic, I., Duketis, E.,Duque, F., Estes, A., Farrar, P., Fernandez, B.A., Folstein, S.E., Fombonne, E.,Freitag, C.M., Gilbert, J., Gillberg, C., Glessner, J.T., Goldberg, J., Green, A.,Green, J., Guter, S.J., Hakonarson, H., Heron, E.A., Hill, M., Holt, R., Howe, J.L.,Hughes, G., Hus, V., Igliozzi, R., Kim, C., Klauck, S.M., Kolevzon, A., Korvatska, O.,Kustanovich, V., Lajonchere, C.M., Lamb, J.A., Laskawiec, M., Leboyer, M., LeCouteur, A., Leventhal, B.L., Lionel, A.C., Liu, X.-Q., Lord, C., Lotspeich, L.,Lund, S.C., Maestrini, E., Mahoney, W., Mantoulan, C., Marshall, C.R.,McConachie, H., McDougle, C.J., McGrath, J., McMahon, W.M., Merikangas, A.,Migita, O., Minshew, N.J., Mirza, G.K., Munson, J., Nelson, S.F., Noakes, C.,Noor, A., Nygren, G., Oliveira, G., Papanikolaou, K., Parr, J.R., Parrini, B., Paton, T.,Pickles, A., Pilorge, M., Piven, J., Ponting, C.P., Posey, D.J., Poustka, A., Poustka, F.,Prasad, A., Ragoussis, J., Renshaw, K., Rickaby, J., Roberts, W., Roeder, K., Roge, B.,Rutter, M.L., Bierut, L.J., Rice, J.P., Salt, J., Sansom, K., Sato, D., Segurado, R.,Sequeira, A.F., Senman, L., Shah, N., Sheffield, V.C., Soorya, L., Sousa, I., Stein, O.,Sykes, N., Stoppioni, V., Strawbridge, C., Tancredi, R., Tansey, K.,Thiruvahindrapduram, B., Thompson, A.P., Thomson, S., Tryfon, A., Tsiantis, J.,Van Engeland, H., Vincent, J.B., Volkmar, F., Wallace, S., Wang, K., Wang, Z.,Wassink, T.H., Webber, C., Weksberg, R., Wing, K., Wittemeyer, K., Wood, S.,Wu, J., Yaspan, B.L., Zurawiecki, D., Zwaigenbaum, L., Buxbaum, J.D.,Cantor, R.M., Cook, E.H., Coon, H., Cuccaro, M.L., Devlin, B., Ennis, S.,Gallagher, L., Geschwind, D.H., Gill, M., Haines, J.L., Hallmayer, J., Miller, J.,Monaco, A.P., Nurnberger, J.I., Paterson, A.D., Pericak-Vance, M.A.,Schellenberg, G.D., Szatmari, P., Vicente, A.M., Vieland, V.J., Wijsman, E.M.,Scherer, S.W., Sutcliffe, J.S., Betancur, C., 2010. Functional impact of global rarecopy number variation in autism spectrum disorders. Nature 466, 368e372.

Qiu, Z., Ghosh, A., 2008. A calcium-dependent switch in a CREST-BRG1 complexregulates activity-dependent gene expression. Neuron 60, 775e787.

Rex, C.S., Chen, L.Y., Sharma, A., Liu, J., Babayan, A.H., Gall, C.M., Lynch, G., 2009.Different Rho GTPaseedependent signaling pathways initiate sequential stepsin the consolidation of long-term potentiation. J. Cell Biol. 186 (1), 85e97.

Reyes, J.C., Barra, J., Muchardt, C., Camus, A., Babinet, C., Yaniv, M., 1998. Alteredcontrol of cellular proliferation in the absence of mammalian brahma(SNF2alpha). EMBO J. 17, 6979e6991.

Ronan, J.L., Wu, W., Crabtree, G.R., 2013. From neural development to cognition:unexpected roles for chromatin. Nat. Rev. Genet. 14 (5), 147e359.

Sanders, S.J., Murtha, M.T., Gupta, A.R., Murdoch, J.D., Raubeson, M.J., Willsey, A.J.,Ercan-Sencicek, A.G., DiLullo, N.M., Parikshak, N.N., Stein, J.L., Walker, M.F.,Ober, G.T., Teran, N.A., Song, Y., El-Fishawy, P., Murtha, R.C., Choi, M.,Overton, J.D., Bjornson, R.D., Carriero, N.J., Meyer, K.A., Bilguvar, K., Mane, S.M.,Sestan, N., Lifton, R.P., Günel, M., Roeder, K., Geschwind, D.H., Devlin, B.,State, M.W., 2012. De novo mutations revealed by whole-exome sequencing arestrongly associated with autism. Nature 485, 237e241.

Santen, G.W.E., Aten, E., Sun, Y., Almomani, R., Gilissen, C., Nielsen, M., Kant, S.G.,Snoeck, I.N., Peeters, E.A.J., Hilhorst-Hofstee, Y., Wessels, M.W., Hollander

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/

A. Vogel-Ciernia, M.A. Wood / Neuropharmacology xxx (2013) 1e1010

den, N.S., Ruivenkamp, C.A.L., van Ommen, G.-J.B., Breuning, M.H., Dunnen,den, J.T., van Haeringen, A., Kriek, M., 2012. Mutations in SWI/SNF chromatinremodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat. Genet. 44,379e380.

Sousa, S.B., Abdul-Rahman, O.A., Bottani, A., Cormier-Daire, V., Fryer, A., Gillessen-Kaesbach, G., Horn, D., Josifova, D., Kuechler, A., Lees, M., MacDermot, K.,Magee, A., Morice-Picard, F., Rosser, E., Sarkar, A., Shannon, N., Stolte-Dijkstra, I.,Verloes, A., Wakeling, E., Wilson, L., Hennekam, R.C.M., 2009. Nicolaides-Bar-aitser syndrome: delineation of the phenotype. Am. J. Med. Genet. A 149A,1628e1640.

Staahl, B.T., Tang, J., Wu, W., Sun, A., Gitler, A.D., Yoo, A.S., Crabtree, G.R., 2013. Ki-netic analysis of npBAF to nBAF switching reveals exchange of SS18 with CRESTand integration with neural developmental pathways. J. Neurosci. 33, 10348e10361.

Su, S.C., Tsai, L.-H., 2012. DNA methylation in cognition comes of age. Nat. Neurosci.15, 1061e1062.

Tea, J.S., Luo, L., 2011. The chromatin remodeling factor Bap55 functions through theTIP60 complex to regulate olfactory projection neuron dendrite targeting.Neural Dev. 6, 5.

Tolstorukov, M., Sansam, C., Lu, P., Koellhoffer, E., Helming, K., Alver, B., Tillman, E.,Evan, J., Wilson, B., Park, P.J., Roberts, C., 2013. Swi/Snf chromatin remodeling/tumor suppressor complex establishes nucleosome occupancy at target pro-moters. Proc. Natl. Acad. Sci. U. S. A. 110 (50), 10165e10170.

Tsurusaki, Y., Okamoto, N., Ohashi, H., Kosho, T., Imai, Y., Hibi-Ko, Y., Kaname, T.,Naritomi, K., Kawame, H.,Wakui, K., Fukushima, Y., Homma, T., Kato,M., Hiraki, Y.,Yamagata, T., Yano, S., Mizuno, S., Sakazume, S., Ishii, T., Nagai, T., Shiina, M.,Ogata, K., Ohta, T., Niikawa, N., Miyatake, S., Okada, I., Mizuguchi, T., Doi, H.,Saitsu, H., Miyake, N., Matsumoto, N., 2012. Mutations affecting components ofthe SWI/SNF complex cause Coffin-Siris syndrome. Nat. Genet. 44, 376e378.

Van Houdt, J.K.J., Nowakowska, B.A., Sousa, S.B., van Schaik, B.D.C., Seuntjens, E.,Avonce, N., Sifrim, A., Abdul-Rahman, O.A., van den Boogaard, M.-J.H.,Bottani, A., Castori, M., Cormier-Daire, V., Deardorff, M.A., Filges, I., Fryer, A.,Fryns, J.-P., Gana, S., Garavelli, L., Gillessen-Kaesbach, G., Hall, B.D., Horn, D.,Huylebroeck, D., Klapecki, J., Krajewska-Walasek, M., Kuechler, A., Lines, M.A.,Maas, S., Macdermot, K.D., McKee, S., Magee, A., de Man, S.A., Moreau, Y.,Morice-Picard, F., Obersztyn, E., Pilch, J., Rosser, E., Shannon, N., Stolte-Dijkstra, I., Van Dijck, P., Vilain, C., Vogels, A., Wakeling, E., Wieczorek, D.,Wilson, L., Zuffardi, O., van Kampen, A.H.C., Devriendt, K., Hennekam, R.,Vermeesch, J.R., 2012. Heterozygous missense mutations in SMARCA2 causeNicolaides-Baraitser syndrome. Nat. Genet. 44, 445e449. S1.

Vogel-Ciernia, A., Matheos, D.P., Barrett, R.M., Kramár, E.A., Azzawi, S., Chen, Y.,Magnan, C.N., Zeller, M., Sylvain, A., Haettig, J., Jia, Y., Tran, A., Dang, R., Post, R.J.,Chabrier, M., Babayan, A.H., Wu, J.I., Crabtree, G.R., Baldi, P., Baram, T.Z.,

Please cite this article in press as: Vogel-Ciernia, A., Wood, M.A., Nemechanisms underlying synaptic plasticity, memory, and intellectual10.1016/j.neuropharm.2013.10.002

Lynch, G., Wood, M.A., 2013. The neuron-specific chromatin regulatory subunitBAF53b is necessary for synaptic plasticity and memory. Nat. Neurosci. 16 (5),552e561.

Vogel-Ciernia, A., Wood, M.A., 2012. Molecular brake pad hypothesis: pulling off thebrakes for emotional memory. Rev. Neurosci. 23, 607e626.

Wang, W., Chi, T., Xue, Y., Zhou, S., Kuo, A., Crabtree, G.R., 1998. Architectural DNAbinding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. Proc. Natl. Acad. Sci. U. S. A. 95, 492e498.

Wang, W., Côté, J., Xue, Y., Zhou, S., Khavari, P.A., Biggar, S.R., Muchardt, C.,Kalpana, G.V., Goff, S.P., Yaniv, M., Workman, J.L., Crabtree, G.R., 1996a. Purifi-cation and biochemical heterogeneity of the mammalian SWI-SNF complex.EMBO J. 15, 5370e5382.

Wang, W., Xue, Y., Zhou, S., Kuo, A., Cairns, B.R., Crabtree, G.R., 1996b. Diversity andspecialization of mammalian SWI/SNF complexes. Genes Dev. 10, 2117e2130.

Wang, X., Nagl, N.G., Wilsker, D., van Scoy, M., Pacchione, S., Yaciuk, P., Dallas, P.B.,Moran, E., 2004. Two related ARID family proteins are alternative subunits ofhuman SWI/SNF complexes. Biochem. J. 383, 319.

Weinberg, P., Flames, N., Sawa, H., Garriga, G., Hobert, O., 2013. The SWI/SNFchromatin remodeling complex selectively affects multiple aspects of seroto-nergic neuron differentiation. Genetics 194, 189e198.

Wolff, D., Endele, S., Azzarello-Burri, S., Hoyer, J., Zweier, M., Schanze, I., Schmitt, B.,Rauch, A., Reis, A., Zweier, C., 2011. In-frame deletion and missense mutations ofthe c-terminal helicase domain of SMARCA2 in three patients with Nicolaides-Baraitser syndrome. Mol. Syndromol. 2, 237e244.

Wu, J.I., Lessard, J., Olave, I.A., Qiu, Z., Ghosh, A., Graef, I.A., Crabtree, G.R., 2007.Regulation of dendritic development by neuron-specific chromatin remodelingcomplexes. Neuron 56, 94e108.

Xue, Y., Canman, J.C., Lee, C.S., Nie, Z., Yang, D., Moreno, G.T., Young, M.K.,Salmon, E.D., Wang, W., 2000. The human SWI/SNF-B chromatin-remodelingcomplex is related to yeast Rsc and localizes at kinetochores of mitotic chro-mosomes. Proc. Natl. Acad. Sci. U. S. A. 97, 13015e13020.

Yan, Z., Cui, K., Murray, D.M., Ling, C., Xue, Y., Gerstein, A., Parsons, R., Zhao, K.,Wang, W., 2005. PBAF chromatin-remodeling complex requires a novel speci-ficity subunit, BAF200, to regulate expression of selective interferon-responsivegenes. Genes Dev. 19, 1662e1667.

Yoo, A.S., Staahl, B.T., Chen, L., Crabtree, G.R., 2009. MicroRNA-mediatedswitching of chromatin-remodelling complexes in neural development. Na-ture 460, 642e646.

Zhao, K., Wang, W., Rando, O.J., Xue, Y., Swiderek, K., Kuo, A., Crabtree, G.R., 1998.Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF com-plex to chromatin after T lymphocyte receptor signaling. Cell 95, 625e636.

Zovkic, I.B., Guzman-Karlsson, M.C., Sweatt, J.D., 2013. Epigenetic regulation ofmemory formation and maintenance. Learn. Mem. 20, 61e74.

uron-specific chromatin remodeling: A missing link in epigeneticdisability disorders, Neuropharmacology (2013), http://dx.doi.org/