gabaa receptors & schizophrenia - university of sydney

GABAA receptors in schizophrenia, Cellscience Reviews, 2008, 5, 180-194

Featured Review Cellscience Reviews Vol 5 No 1

ISSN 1742-8130

The Role of GABAA Receptors in Schizophrenia

Tina Hinton & Graham A.R. Johnston Dept. of Pharmacology, School of Medical Sciences, The University of Sydney & Schizophrenia Research Institute,

NSW, Australia

Received 16th July © Cellscience 2008

Schizophrenia is a neurodevelopmental disorder triggered by environmental factors in the pre-, peri- or postnatal periods and manifesting as changes in brain chemistry and morphology. A deficit in the GABAergic system is strongly implicated in schizophrenia, resulting in perturbed inhibitory transmission. GABAA receptors are altered in post-mortem brains of persons with schizophrenia. Increased binding to the orthosteric binding site and decreased binding to the benzodiazepine site have been observed in a number of brain regions, while α1 and α2 subunit expression is increased and γ2 subunit expression is decreased in the prefrontal cortex. While the cause of these changes is not known, it is evident that they may be due to an early life insult, such as infection or stress, which alters the maturational expression of GABAA receptors and thus the balance between inhibition and excitation in the developing brain. As GABAergic transmission is vital in modulating cortical activity, the altered receptor activity and pharmacology would disrupt normal neural processing, resulting in an imbalance in other systems, and symptoms of schizophrenia.

Schizophrenia

Schizophrenia is a debilitating syndrome that commonly strikes individuals in late adolescence and has a potentially chronic course. While there is a clear genetic component to schizophrenia, environmental factors are expected to play a major role

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GABAA receptors & schizophrenia

in precipitation of the illness (Harrison, 1997).

Schizophrenia is a neurodevelopmental disorder, thought to arise from aberrant neural development, triggered by environmental factors in the pre-, peri- or postnatal periods (Harrison, 1997). As this occurs in early corticogenesis, changes in brain chemistry and morphology result (Lafargue & Brasic, 2000). These changes lead to modified patterns of neural communication, which contribute to impaired information processing and behavioural changes in adulthood (Benes et al., 1992).

The GABA Receptors

The GABAergic system is principally involved in the balance of excitation and inhibition in the brain. GABA is synthesised in 20-30% of all CNS neurons (Varju et al., 2001) and is the primary transmitter at 25-50% of synapses in mammalian brain (Petroff & Rothman, 1998). Its ubiquitous presence means that almost all neurons express GABA receptors, and either release GABA or are innervated by neurons which do (Koella, 1981; Olsen, 1991). For these reasons it is expected that most brain functions involve GABAergic transmission (Koella, 1981). Consequently, the role of GABA in normal information processing is crucial, as GABA acts to keep processes of the CNS under control (Koella, 1981; Roberts, 1984; Roberts, 1991).

GABA is a flexible molecule that adopts many conformations in order to bind to receptors, through which its inhibitory effects are mediated (Johnston, 1996). GABA is the endogenous neurotransmitter for three known classes of receptors: GABAA, GABAB and GABAC receptors. The GABA receptor classes are delineated on the basis of structural, physiological and pharmacological differences. GABAA and GABAC receptors are ligand gated ion channels (ionotropic), while the GABAB receptors are G-protein coupled receptors (metabotropic). Of the GABA receptors, GABAA receptors are the most complex, and the abundance of allosteric binding sites on these receptors places them as important functional and therapeutic targets in the brain. For this reason, the current review focuses on the GABAA receptors.

GABAA receptors are composed of five membrane-spanning subunits which form a central pore, the ion channel (Karlin, 2002; Macdonald & Olsen, 1994; Unwin, 1989). These receptors are heterooligomeric, made up of a combination of five subunits from a possible sixteen (α1-6, β1-3, γ1-3 (with two splice variants, γ2Long and γ2Short), δ, ε and θ) identified in the mammalian brain (Chebib & Johnston, 2000). The usual stoichiometry is 2α, 2β and 1γ subunits, in the arrangement γαβαβ (Minier & Sigel, 2004). GABAA receptors contain orthosteric binding sites for


direct agonists such as GABA at the interface of the α and β subunits (Baur & Sigel, 2003), as well as binding sites for a number of allosteric modulators including benzodiazepines, barbiturates, ethanol, general anaesthetics, flavonoids and steroids (Chebib & Johnston, 2000). The diversity of GABAA receptor subunits means that many subtypes of GABAA receptors exist, and the function and pharmacological sensitivity of these subtypes is determined by their subunit composition. GABAA receptors mediate both fast and tonic GABAergic inhibition and changes in the function and expression of these receptors have been strongly implicated in schizophrenia.

Changes in GABAA Receptors in Schizophrenia

Evidence for alterations in GABAA receptors in schizophrenia is strong. Binding studies have shown increased binding of high affinity [3H]muscimol or [3H]GABA to the total population of GABAA receptors in the dorsolateral prefrontal cortex, caudate nucleus, posterior and anterior cingulate cortices, superior temporal gyrus and hippocampal formation of post-mortem schizophrenic brains compared with controls (Benes et al., 1992; Benes et al., 1996a; Benes et al., 1996b; Dean et al., 1998; Dean et al., 1999; Deng & Huang, 2006; Hanada et al., 1987; Newell et al., 2007; Owen et al., 1981). This has been supported by findings of increased GABAA receptor α1, α2, α3 and α5 subunit mRNAs, and α1 and β2/3 subunit proteins, in the schizophrenic prefrontal cortex (Impagnatiello et al., 1998; Ishikawa et al., 2004b; Ohnuma et al., 1999; Pesold et al., 1998; Volk et al., 2002).

An increase in binding to the orthosteric site on GABAA receptors signifies elevated total GABAA receptor number in the regions examined in the schizophrenic brain. Moreover, α1- and α2-containing GABAA receptors are preferentially localized to pyramidal cells in the cortex (Ishikawa et al., 2004b; Wisden et al., 1992). Thus, an increase in binding and subunit expression possibly reflects a compensatory up-regulation of GABA receptors in response to defective inhibitory modulation and input to pyramidal cells, caused by a reduced number of inhibitory interneurons, or deficient transport or release of GABA in these regions (Benes et al., 1992; Benes et al., 1996b; Benes et al., 1997; Ishikawa et al., 2004b; Weickert & Kleinman, 1998).

On the other hand, studies of the sub-populations of GABAA receptors that bind benzodiazepines have found no change in benzodiazepine binding (Benes et al., 1997; Owen et al., 1981; Pandey et al., 1994; Pandey et al.,1997; Reynolds & Stroud, 1993), or decreased binding in brain regions such as the caudate, anterior cingulate cortex, somatomotor cortex, hippocampus, cerebellar cortex and globus pallidus (Squires et al., 1993) of schizophrenic brain. Moreover, decreased mRNA


and protein expression of the γ2 subunit, required for high-affinity benzodiazepine binding (Pritchett et al., 1989), has been found in post-mortem schizophrenic brain compared to control (Akbarian et al., 1995b; Huntsman et al., 1998; Pesold et al., 1998). Interestingly, no change in γ1 or γ3 subunit proteins was observed in prefrontal cortex of schizophrenic compared to control brains (Ishikawa et al., 2004a). Thus, the subset of GABAA receptors sensitive to benzodiazepines may be preferentially downregulated or their subunit composition altered in schizophrenia. Alternatively, an increase in GABAA receptor subtypes devoid of the γ2 subunit, that is, receptors that do not bind benzodiazepines with high affinity, may occur in schizophrenia (Pesold et al., 1998).

A major problem with studies of post-mortem human brain is the probable influence of antipsychotic drugs on receptor expression. For example, when schizophrenic patients were analysed as antipsychotic-medicated or antipsychotic-free, those that were medicated showed significantly lower [3H]flumazenil binding to benzodiazepine sites compared to medication-free patients and normal controls (Pandey et al., 1997). A number of animal studies have therefore been conducted to examine whether the receptor alterations observed in schizophrenia are due to drug therapy. Investigations have shown that in the same animals, longer-term antipsychotic treatment does not alter the total population of GABAA receptors (determined by [3H]muscimol binding), but it does increase the density of benzodiazepine-sensitive receptors (Skilbeck et al., 2007; Skilbeck et al., 2008). This suggests that antipsychotic administration results in a reshuffling of GABAA receptor subunits, leading to a greater proportion of receptors available for benzodiazepine binding. Moreover, these changes are not consistent with those observed in post-mortem human brain, suggesting that the disease pathophysiology alters GABAA receptors in a manner that may be compensated for by antipsychotic drugs.

GABA-mimetic agents such as muscimol and THIP fail to ameliorate symptoms of schizophrenia, and in some cases produce psychotomimetic responses in humans (Costa, 1992; Guidotti et al., 2005) and exacerbate the symptoms of schizophrenia (Guidotti et al., 2005; Tamminga et al., 1978). Potentially, the pathological up-regulation of GABAA receptors in schizophrenia may lead to hypersensitivity of post-synaptic receptors to GABA-mimetic agents. On the other hand, there is some evidence for a therapeutic effect of GABAA receptor allosteric modulators such as benzodiazepines in schizophrenia, as well as drugs which inhibit GABA breakdown, thus increasing synaptic GABA concentrations (see Wassef et al., 1999, for review). These drugs demonstrate therapeutic effects when used as monotherapy and when administered in combination with antipsychotics (Guidotti et al., 2005; Wassef et


al., 1999). Thus, modification of GABAergic activity through allosteric modulation or inhibition of its breakdown, rather than direct agonist action, may be a preferable means of attenuating symptoms of schizophrenia, or adverse effects of antipsychotic compounds. GABAergic agents may also provide additional therapeutic benefit in combination with antipsychotics (Guidotti et al., 2005; Wassef et al., 1999).

What Do These GABAA Receptor Changes Mean?

Changes in GABAA receptors in schizophrenic brain may represent a primary pathogenesis, such that modifications to GABAA receptor subunit assembly and/or structure contribute to the symptoms of schizophrenia (Costa, 1992). Alternatively, the receptor alterations may be due to the postulated downregulation in presynaptic GABAergic function, as evidenced through decreased GABA synthesis or release (Akbarian et al., 1995a; Guidotti et al., 2000; Sherman et al., 1991; Volk et al., 2000), decreased GABA concentration (Ohnuma et al., 1999) and reduced integrity of inhibitory interneurons (Beasley & Reynolds, 1997; Beasley et al., 2002; Benes et al., 1992; Lewis et al., 1999; Lewis et al., 2001; Reynolds et al., 2002), or a combination of these.

Further, changes in GABAA receptors in schizophrenia may arise from aberrations in other neurotransmitter systems that interact with GABA. Since GABA is ubiquitous throughout the CNS and plays an important role in counterbalancing glutamate-mediated neuronal excitation, abnormalities in the interaction between these two systems might disrupt several brain functions, including cognitive function (Costa, 1992). Altered communication between glutamatergic pyramidal and GABAergic local circuit neurons would result in a loss of inhibitory tone, with consequent disinhibition of excitatory pyramidal cells, leading to increased excitatory output to other areas of the brain (Benes et al., 1996b). An up-regulation of post-synaptic GABA receptors may compensate for reduced inhibition to some extent (Benes et al., 1996b). Alternately, or concurrently, the interaction between dopamine and GABA may be compromised by a loss of inhibitory tone in schizophrenia. It is thought that decreased GABAergic function may lead to increased dopaminergic activity. Dopamine receptors are localised to GABAergic interneurons in rat and primate brain (Mrzljak et al., 1996; Vincent et al., 1993). Dopaminergic afferents also terminate on cortical GABA interneurons to exert an inhibitory effect, thus exacerbating a deficiency in GABAergic neurotransmission (Benes et al., 1992). It has been suggested that antipsychotic-mediated dopamine receptor antagonism may permit normal release of GABA, alleviating symptoms of schizophrenia effected by deficient GABAergic neurotransmission (Benes et al., 1992). GABAergic transmission is vital in modulating cortical activity, thus altered


activity would disrupt normal neural processing, resulting in an imbalance in other systems, and symptoms of schizophrenia.

In any case, whether due to primary or secondary pathogenesis, altered GABAA receptor number or subunit composition in cortical regions important for associative, integrative processing may lead to the disruptions of higher cognition observed in schizophrenia (Akbarian et al., 1995a; Lee & Tobin, 1995).

Whilst the evidence for changes in GABA receptors in schizophrenia is clear, the functional consequence of these changes is still unclear. Some studies have provided evidence for a specific role for GABA receptors system in schizophrenic symptoms. For example, binding of [11C]Ro15-4513, a high affinity ligand for the benzodiazepine site of α5-containing GABAA receptors, in the prefrontal cortex was negatively correlated with negative symptom scores in schizophrenic patients, suggesting a role for α5-containing GABAA receptors in the negative symptoms of schizophrenia (Asai et al., 2008). Reduced [123I]iomazenil binding was correlated with poorer cognitive function in schizophrenic patients during neuropsychological tasks measured using single photon emission tomography (SPECT; Ball et al., 1998). Busatto and colleagues (1997) also demonstrated reduced [123I]iomazenil binding in relation to the severity of negative symptoms in the medial frontal lobe and positive symptoms in the left temporal lobe in schizophrenia.

More recent studies have implicated GABAA receptors in the sensorimotor gating deficits observed in schizophrenia. α3 and α5 subunits appear to modulate expression of prepulse inhibition (a model of sensorimotor gating) since α3 and α5 subunit knock-down mice separately showed deficits in prepulse inhibition and increased locomotor activity (Hauser et al., 2005; Yee et al., 2005). The hippocampus plays a role in sensorimotor gating, so GABAA receptor abnormalities in this region may be crucial to deficits in sensorimotor gating in schizophrenia. These findings also suggest that agents selective for GABAA receptors containing α3 or α5 subunits may constitute effective treatments for sensorimotor gating deficits whilst lacking the sedative side effects seen with similar non-selective agents or classical antipsychotics (Mohler, 2006).

Why Are GABAA Receptors Altered in Schizophrenia?

The actual cause of alterations in GABAA receptors observed in schizophrenia is unknown, however environmental and neurodevelopmental factors must be considered. What is not apparent is when the selective changes in GABA receptors become manifest, although some research has been carried out to address this.


Development and GABAA Receptors in Schizophrenia

GABAA receptors maintain a critical role in brain development, facilitating neuronal migration and regulating differentiation and synaptogenesis of pyramidal cells (Behar, et al., 2000; Keverne, 1999). GABAA receptors are excitatory during early postnatal development, forming before glutamatergic synapses (Ben-Ari, 2002). The switch from excitatory to inhibitory action appears to coincide with the expression of chloride channels during early development (Yamada et al., 2004). In early postnatal days, NKCC1 channels (which accumulate chloride) are highly expressed, but decrease as expression of KCC2 channels (which extrude chloride) increase, promoting the maturation of GABAergic inhibition (Yamada et al., 2004). Activation of excitatory GABA receptors would lead to an increase of intracellular calcium, and the depolarisation can remove the voltage-dependent magnesium block from glutamatergic NMDA receptors (Ben-Ari, 2002). Such excitatory activity may increase vulnerability to cell damage following neonatal insults such as stress or hypoxia. An interruption in the appropriate GABAergic/glutamatergic balance would also upset NMDA receptor-mediated long-term potentiation necessary for differentiation and stabilisation of synaptic contacts during cortical development (Lafargue & Brasic, 2000).

In early development the α2 and α3 subunits are highly expressed, and there appears to be an α2/α1 subunit switch in many brain regions after the first postnatal weeks, as the α1 subunit becomes more abundant, a characteristic which persists into adulthood (Fritschy et al., 1992; McKernan et al., 1991). Both the α1 and α2 subunit mRNAs are increased in the prefrontal cortex in schizophrenia, although the α2 subunit is increased by 100 times the control levels (Volk et al., 2002). This suggests that perhaps the more ‘immature’ subunit expression pattern persists in schizophrenic brain. Although yet to be investigated in regions other than the hippocampus, the altered subunit expression may arise from stressful events in early life (maternal or neonatal), perhaps disrupting the α2/α1 switch and shifting the ratios of α2 and α1 subunits in the adult brain. This is also significant as the α2 subunit is differentially localised to the α1 subunit and confers different pharmacological sensitivity (Volk et al., 2002). α1 Subunits in the cortex are expressed on cell bodies and proximal dendrites of pyramidal cells while α2 subunits are preferentially located on cell bodies and the axon-initial segment of pyramidal cells (Guidotti et al., 2005). The more ‘immature’ subunit expression pattern in schizophrenic brain may therefore lead to aberrant glutamatergic cortical output. Given the different sensitivity of the various α subunits to GABA and


allosteric modulators (Barnard et al., 1998; Levitan et al., 1988), this altered pattern of subunit expression would alter the pharmacology of GABAA receptors in the schizophrenic brain. The implications of a disturbance in GABAergic transmission are thus considerable.

Infection and GABAA Receptors in Schizophrenia

Prenatal exposure to infection has been associated with increased incidence of schizophrenia (Nyffeler et al., 2006). Nyffeler et al. (2006) have shown that augmenting cytokines through injection during pregnancy significantly increases α2 subunit immunoreactivity in rat corticolimbic structures. While altered α2 subunit expression has not yet been investigated in these structures in post-mortem schizophrenic brain, increased expression has been demonstrated in other cortical structures (Volk et al., 2002), thus prenatal infection may explain some of these changes in GABAA receptors in schizophrenia.

Stress and GABAA Receptors in Schizophrenia

Stress is an important environmental factor that has been implicated in schizophrenia. Studies suggest that chronic early-life stress increases GABA receptor activity. Chronic neonatal stress through maternal deprivation increased [3H]GABA binding to whole rat brain homogenates by 10% measured 100 days later (Bolden et al., 1990). This emphasises that alterations in GABAA receptors during neural development may have enduring effects, lending vulnerability to schizophrenia.

Stress involves activation of the hypothalamic-pituitary-adrenal axis, causing release of glucocortocoids (corticosterone in rats, cortisol in humans; Corcoran et al., 2003). Neurosteroids are also released during stress, and both neurosteroids and glucocorticoids allosterically modulate GABAA receptors (Johnston et al., 1987; Purdy et al., 1991). Neurosteroids enhance tonic inhibition mediated by extrasynaptic GABAA receptors containing the δ subunit (Stell et al., 2003). Increased α1 subunit mRNA following chronic stress coupled with acute corticosteroid exposure has been observed in dentate gyrus granule cells (Qin et al., 2004), while decreased γ2 subunit mRNA and benzodiazepine binding were found following chronic pre- and post-natal corticosterone exposure in rat hippocampus (Stone et al., 2001). Thus it appears chronic stress (or mediators of stress) in the early developmental phase may modify the HPA axis to create long term changes in GABAA receptor binding and subunit expression that mirror those changes observed


in post-mortem schizophrenic brain. Modified GABAergic activity by stress is also related to altered pharmacology of drugs interacting with the receptors (Briones-Aranda et al., 2005).

Conclusion

In addition to the well-known involvement of dopamine and glutamate systems in schizophrenia, we must add GABA systems. Changes in GABAA receptors play an important role in aspects of schizophrenia. There is strong evidence for a subtype-selective increase in the number of such receptors in the post-mortem schizophrenic brain. While the cause of these changes is not known, it is evident that they may be due to an early life insult, such as infection or stress, which alters the maturational expression of GABAA receptors and thus the balance between inhibition and excitation in the developing brain. A change in GABAA receptors due to antipsychotic drug therapy is also an important issue, and development of subtype-selective therapies for GABAA receptors is a current challenge.

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gabaa receptors & schizophrenia - university of sydney

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