RESEARCH ARTICLES◥

NEUROIMMUNOLOGY

The maternal interleukin-17a pathwayin mice promotes autism-likephenotypes in offspringGloria B. Choi,1* Yeong S. Yim,1* Helen Wong,2,3* Sangdoo Kim,4 Hyunju Kim,4

Sangwon V. Kim,5 Charles A. Hoeffer,2,3† Dan R. Littman,5,6† Jun R. Huh4,5†

Viral infection during pregnancy has been correlated with increased frequency of autismspectrum disorder (ASD) in offspring. This observation has been modeled in rodentssubjected to maternal immune activation (MIA). The immune cell populations critical inthe MIA model have not been identified. Using both genetic mutants and blockingantibodies in mice, we show that retinoic acid receptor–related orphan nuclear receptorgamma t (RORgt)–dependent effector T lymphocytes [for example,T helper 17 (TH17) cells]and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-inducedbehavioral abnormalities in offspring. We find that MIA induces an abnormal corticalphenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggestthat therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce thelikelihood of bearing children with inflammation-induced ASD-like phenotypes.

Several studies have suggested that viral in-fection of women during pregnancy corre-lates with an increased frequency of autismspectrum disorder (ASD) in the offspring(1–6). In the rodent maternal immune ac-

tivation (MIA) model of this phenomenon (7), off-spring from pregnant mice infected with virus orinjected intraperitoneally with synthetic double-stranded RNA (dsRNA) [poly(I:C)], a mimic ofviral infection, exhibit behavioral symptomsreminiscent of ASD: social deficits, abnormalcommunication, and repetitive behaviors (8). Thelper 17 (TH17) cells are responsible for immuneresponses against extracellular bacteria and fungi,and their dysregulation is thought to underlienumerous inflammatory and autoimmune dis-eases (9), such as asthma, rheumatoid arthritis,psoriasis, inflammatory bowel disease (IBD), andmultiple sclerosis. The transcription factor reti-noic acid receptor–related orphan nuclear recep-tor gamma t (RORgt) is expressed in several celltypes in the immune system. It is a key transcrip-tional regulator for the development of TH17 cells,

aswell as gd Tcells and innate lymphoid cells (suchas ILC3) that express TH17 cell–like cytokines, inboth humans and mice (10–13).TH17 cells and their cytokine mediators have

been suggested to have a role in ASD. For exam-ple, elevated levels of interleukin-17a (IL-17a), thepredominant TH17 cytokine, have been detectedin the serumof a subset of autistic children (14, 15).A genome-wide copynumber variant (CNV) analy-sis identified IL17A as one ofmany genes enrichedin autistic patients (16). Similarly, in theMIAmousemodel, CD4+T lymphocytes fromaffectedoffspringproduced higher levels of IL-17a upon in vitroactivation (17, 18). Although these data suggestthat TH17 cells may be involved in ASD patients,whether TH17 cells are the specific immune cellpopulation that is necessary for MIA phenotypesis unknown.Here, we show thatmaternal RORgt-expressing proinflammatory T cells, a majorsource of IL-17a, are required in the MIA modelfor induction of ASD-like phenotypes in off-spring. Consistent with this notion, antibodyblockade of IL-17a activity in pregnant miceprotected against the development of MIA-induced behavioral abnormalities in the offspring.Also, we found atypical cortical developmentin affected offspring, and this abnormality wasrescued by inhibition of maternal TH17–IL-17apathways.

Elevated fetal brain IL-17Ra mRNAfollows increased maternal IL-17a in MIA

Pregnant mothers injected with poly(I:C) on em-bryonic day 12.5 (E12.5) had strong induction ofserum cytokines IL-6, tumor necrosis factor-a(TNF-a), interferon-b (IFN-b), and IL-1b at 3 hours,comparedwith phosphate-buffered saline (PBS)–

injected control dams (Fig. 1A and fig. S1, A toC). Additionally, poly(I:C) injection resulted ina strong increase of serum IL-17a at E14.5 (Fig.1B). On the other hand, poly(I:C) did not affect thelevels of the anti-inflammatory cytokine IL-10 inthe serum nor in placenta and decidua extracts(fig. S1D). It was previously shown that the pro-inflammatory effector cytokine IL-6, a key factorfor TH17 cell differentiation (19), is required inpregnant mothers for MIA to produce ASD-likephenotypes in the offspring (7). We found thatpoly(I:C) injection into pregnant dams lackingIL-6 [IL-6 knockout (KO)] failed to increase theserum levels of IL-17a at E14.5, consistent withIL-6 acting upstreamof IL-17a. Conversely, recom-binant IL-6 injections intowild-type (WT)motherswere sufficient to induce IL-17a levels compara-ble to those of poly(I:C)-injectedWTmothers (fig.S1E). Placenta- and decidua-associated mono-nuclear cells, isolated from poly(I:C)-treated ani-mals at E14.5 and cultured for 24 hours, expressedamounts of IL-6 mRNA similar to those of PBScontrols (Fig. 1C). In contrast, IL-17amRNAexpres-sion in these cells was strongly up-regulated bypoly(I:C) injection (Fig. 1D). This increase inmRNAexpression was correlated with enhanced secre-tion of IL-17a by placenta- anddecidua-associatedmononuclear cells from poly(I:C)-treated dams(Fig. 1E), upon ex vivo stimulation with phorbol-myristate acetate (PMA) and ionomycin, whichmimics T cell receptor (TCR) activation. IL-17ainduction was specific to the placenta and de-cidua, as small intestine mononuclear cells frompoly(I:C)-treated pregnant dams did not secretemore IL-17a than those from PBS-treated con-trols (fig. S1F).We also observed that expression of the IL-17a

receptor subunit A (IL-17Ra) mRNA, but not sub-unit C (IL-17Rc) mRNA, was strongly augmentedin the fetal brain upon induction of MIA (Fig. 1, Fand G). By in situ hybridization, IL-17Ra mRNAwas detected in the mouse cortex, and its ex-pression was strongly up-regulated in E14.5 fetalbrains after poly(I:C) injection of pregnant dams(Fig. 1, H and I). The in situ probe detectingendogenous expression of IL-17Ra was specific, asit did not produce detectable signal in E14.5 fetalbrain that lacks IL-17Ra (fig. S2).

Maternal IL-17a promotes abnormalcortical development in offspring

We next investigated if pathological activation ofthe IL-17 pathway in pregnant mothers affectsfetal brain development and subsequently con-tributes to the ASD-like behavioral phenotypesin offspring. To test this hypothesis, we pretreatedpregnantmothers with isotype control or IL-17a–blocking antibodies before injecting them withPBS or poly(I:C) (fig. S3). We then examined cor-tical development in the fetus for the followingreasons: (i) Poly(I:C) injection ofmothers increasesIL-17Ra expression in the cortex of the fetal brain(Fig. 1, H and I); (ii) cortical development startsat about E11 (20), which aligns well with the timepoints of potential fetal exposure to MIA (7); (iii)disorganized cortex and focal patches of abnor-mal laminar cytoarchitecture have been found in

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1The McGovern Institute for Brain Research, Department ofBrain and Cognitive Sciences, Massachusetts Institute ofTechnology, Cambridge, MA 02139, USA. 2Center for NeuralScience, New York University, New York, NY 10003, USA.3Institute for Behavioral Genetics, Department of IntegratedPhysiology, University of Colorado, Boulder, CO 80303, USA.4Division of Infectious Diseases and Immunology andProgram in Innate Immunity, Department of Medicine,University of Massachusetts Medical School, Worcester, MA01605, USA. 5The Kimmel Center for Biology and Medicineof the Skirball Institute, New York University School ofMedicine, New York, NY 10016, USA. 6Howard HughesMedical Institute, New York, NY 10016, USA.*These authors contributed equally to this work. †Correspondingauthor. E-mail: charles.hoeffer@colorado.edu (C.A.H.); dan.littman@med.nyu.edu (D.R.L.); jun.huh@umassmed.edu (J.R.H.)

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the brains of ASD patients (21, 22); and (iv) MIAhas been shown to affect cortical development(23, 24). We analyzed cortical lamination, an or-derly layered structure of the cortex, in fetal brainsat E14.5 and E18.5, as well as in the adult brain,using antibodies specific for proteins expressed inthe cortex in a layer-specific manner (25): specialAT-rich sequence-binding protein 2 (SATB2) (26),T-brain-1 (TBR1) (27), and chicken ovalbumin up-stream promoter transcription factor–interactingprotein 2 (CTIP2) (28). MIA led to delayed ex-pression of SATB2 at E14.5 compared with fetusesof control animals (Fig. 2, A and C). At E18.5, MIAresulted in a patch of disorganized cortical cyto-architecture (Fig. 2, B andD toG) but did not affectcortical thickness of the fetal brains (Fig. 2H). Thissingular patch of disorganized cortex occurredat a similar medial-lateral position in a majorityof E18.5 fetal brains (Fig. 2, E andG) derived frommothers injected with poly(I:C) but not those in-jectedwith PBS. The abnormal expressionpatternsof SATB2, TBR1, and CTIP2 were maintained inadult MIA offspring (fig. S4). Note that normalexpression of these cortical layer–specific markers,as well as laminar cortical organization, werelargely preserved in the offspring of poly(I:C)-

injected mothers pretreated with IL-17a–blockingantibody (Fig. 2, A to D, and fig. S4).Pretreatment with IL-17a–blocking antibody

also suppressed the MIA-mediated increase inIL-17Ra mRNA expression in fetal brain at E14.5(Fig. 1F). This suppression was accompanied by areduction in maternal serum IL-17a (Fig. 1B),which indicated that the up-regulation of IL-17RamRNA in fetal brains requires maternal IL-17asignaling. Of note, IL-17a antibody blockade of theIL-17a–IL-17Ra signaling pathway did not result ina concomitant increase of the serum IL-10 levels,and IL-17amRNA expression was not detected infetal brain at E14.5, regardless of poly(I:C) injec-tion. Together, these data demonstrate that thematernal IL-17a–dependent pathway mediatesdisorganized cortical phenotypes in offspring af-ter in uteroMIA and suggest that this may be dueto exposure of the fetus and its brain to increasedlevels of IL-17a.

Maternal IL-17a promotes ASD-likebehavioral abnormalities in offspring

We next tested the functional relevance of thematernal IL-17a pathway for MIA-induced ASD-like behavioral abnormalities in offspring (fig.

S3). We first assessed MIA offspring for abnor-mal communication by measuring pup ultra-sonic vocalization (USV) responses (29). Afterseparation from mothers, pups from poly(I:C)-injected mothers pretreated with immunoglo-bulin G (IgG) isotype control antibody emittedmore USV calls than those from PBS-injectedmothers (Fig. 3A), in agreement with previousstudies (29, 30). Some studies have reportedreduced USV calls upon MIA (8, 31), but theseopposite effects may reflect differences in meth-odological approaches, including dose and num-ber of exposures to poly(I:C), as well as timing ofpoly(I:C) administration. Altogether, these resultsindicate that MIA induces abnormal USV inoffspring. Pretreating poly(I:C)-injected motherswith IL-17a–blocking antibody resulted in off-spring that emitted a similar number of USV callsas the pups from PBS-injected control mothers(Fig. 3A), which demonstrated that IL-17a–mediated signaling events are necessary for theMIA-induced abnormal USV phenotype. As pre-viously reported (7, 8), we found that prenatalexposure toMIA also caused social interaction de-ficits in adult offspring (Fig. 3B). This defect wasfully rescued in offspring frompoly(I:C)-injected

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Fig. 1. IL-17a increase in mothers subjected to MIA leads to elevatedIL-17Ra mRNA expression in the offspring. (A) Serum concentrations ofIL-6 (n = 3 to 5 mice per group, two independent experiments) at 3 or 24 hoursafter PBS or poly(I:C) injection into pregnant dams at E12.5. (B) Serum con-centrations of maternal IL-17a (n = 4 to 8 mice per group, two independentexperiments) at E14.5 in PBS- or poly(I:C)-injected mothers, pretreated withor without anti–IL-17a. (C and D) Relative IL-6 (C) and IL-17a (D) mRNA ex-pression in cells isolated from placenta or decidua of PBS- or poly(I:C)-treatedmothers at E14.5 and cultured in vitro for 24 hours. The results are repre-sentative of three independent experiments. For each probe set, relative mRNAexpression of one biological replicate from PBS-treated dams was set at 1.Real-time PCR analysis of relative expression of indicated genes compared withthe level of glyceraldehyde-3-phosphate dehydrogenase in cells from PBS-

treated dams. (E) Supernatant concentrations of IL-17a from ex vivo culturedmononuclear cells, isolated from placenta or decidua of PBS- or poly(I:C)-treatedpregnant dams. Stim refers to PMA and ionomycin stimulation. (FandG) RelativeIL-17Ra (F) and IL-17Rc (G) mRNA levels in E14.5 male fetal brain, derived fromPBS- or poly(I:C)-injected mothers, pretreated with isotype control (Cont) oranti–IL-17a.The relative mRNA fold change, compared with the PBS- and Cont-treated groups, is plotted on the y axis (n = 7 for all groups; two or three in-dependent experiments). (H) In situ hybridization with an IL-17Ra RNA probe inE14.5 male fetal brains derived from PBS- or poly(I:C)-injected mothers. Imagesare representative of four independent experiments. DAPI, 4′,6′-diamidino-2-phenylindole. (I) Relative signal intensity for images shown in (H). Scale bar,100 mm. (A), (B), (E), (F), and (G) One-way analysis of variance (ANOVA) withTukey’s post hoc tests. (C), (D), and (I) Student’s t test. **P < 0.01. Means ± SEM.

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mothers pretreated with IL-17a–blocking anti-body (Fig. 3B). Repetitive and perseverative be-haviors are another core feature in ASD that wetested next in our experimental mice using the

marble-burying assay (32). Offspring from poly(I:C)-injectedmothers displayed enhancedmarbleburying compared with offspring from PBS-injected mothers (Fig. 3C), consistent with previ-

ous studies (7, 29). Pretreatment with IL-17a–blocking antibody of poly(I:C)-injected mothersrescuedmarble-burying behavior in the offspring(Fig. 3C). Notably, distinct behavioral phenotypes

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Fig. 2. The IL-17a pathway promotes abnormal cortical development inthe offspring of pregnant dams after MIA. (A) Immunofluorescence stainingof SATB2 (a marker of postmitotic neurons in superficial cortical layers) inE14.5 male fetal brain, derived from PBS- or poly(I:C)-injected mothers, pre-treated with isotype control (Cont) or anti–IL-17a. MZ, marginal zone; CP,cortical plate; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.(B) Staining of SATB2 and TBR1 (a marker restricted to deeper cortical lay-ers) in E18.5 male fetal brains from animals treated as in (A). Cortical layers:II to IV, V, and VI. (C) Quantification of SATB2 intensity in the cortical plateof E14.5 fetal brains (n = 8 for all groups; three independent experiments).(D) Quantification of TBR1- and SATB2-positive cells in a 300 × 300 mm2 re-gion of interest (ROI) centered on the malformation in the cortical plate ofE18.5 fetal brains {n = 20 (PBS, Cont); n = 20 (PBS, anti–IL-17a); n = 24 [poly(I:C),

Cont]; n = 20 [poly(I:C), anti–IL-17a]; five independent experiments}. (E) Thespatial location of the cortical patch in E18.5 male fetal brains from poly(I:C)-injected mothers pretreated with control antibodies {n = 20 [poly(I:C), Cont]}.(F) The disorganized patches of cortex observed in fetuses from poly(I:C)-injected mothers were categorized into groups based on morphology: Pro-trusions, intrusions, or other abnormal patterns and their representativeimages are shown. (G) Percentage of the cortical patches in each category{n = 24 [poly(I:C), Cont]}. (H) Thickness of the cortical plate in E18.5 fetalbrains, derived from PBS- or poly(I:C)-injected mothers, pretreated withisotype control or anti–IL-17a (n = 20 for all groups; five independentexperiments). Scale bars in (A), (B), and (F), 100 mm.One-way ANOVA (C) and(H) and two-way ANOVA (D) with Tukey’s post hoc tests. **P < 0.01 and *P <0.05. Means ± SEM.

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observed among different treatment groups werenot due to differences in activity or arousal, astotal distances moved during the sociability test

were indistinguishable (Fig. 3D). Moreover, dif-ferent treatment groupsdisplayed comparable gen-der ratios, litter sizes, and weights (fig. S5). Taken

together, these data indicate that the IL-17a path-way in pregnant mice is crucial in mediating theMIA-induced behavioral phenotypes in offspring.

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Fig. 3. The IL-17apathway promotesASD-like phenotypesin the MIA offspring.(A) USV assay. At P9,pups from the indi-cated experimentalgroups wereseparated from theirmothers to elicit USVcalls. The number ofpup calls is plotted onthe y axis {n = 25(PBS, Cont); n = 28(PBS, anti–IL-17a); n =38 [poly(I:C), Cont]; n = 34 [poly(I:C), anti–IL-17a]; from six or sevenindependent experiments}. (B) Social approach behavior. Graphed as asocial preference index (% time spent investigating social or inanimatestimulus out of total object investigation time) {n = 15 (PBS, Cont); n = 15(PBS, anti–IL-17a); n = 16 [poly(I:C), Cont]; n = 20 [poly(I:C), anti–IL-17a];from six or seven independent experiments}. (C) Marble-burying behavior.

Percentage of the number of buried marbles is plotted on the y axis {n = 15(PBS, Cont), n = 15 (PBS, anti–IL-17a), n = 15 [poly(I:C), Cont]; n = 20 [poly(I:C),anti–IL-17a]; from six or seven independent experiments}. (D) Total distancetraveled during social approach behavior. (A), (C), and (D) One-way ANOVAwith Tukey’s post hoc tests. (B) Two-way ANOVA with Tukey’s post hoc tests.**P < 0.01 and *P < 0.05. Means ± SEM.

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Fig. 4. RORgt expression in maternal Tcells is required for manifestationof ASD-like phenotypes in the MIA model. (A) SATB2 and TBR1 stainingin the cortex of E18.5 male fetal brains after MIA induction with poly(I:C) inmothers with the indicated genotypes. Cortical layers: II to IV, V, and VI.Images are representative of three independent experiments. Scale bar, 100 mm.(B) Quantification of TBR1- and SATB2-positive cells in a 300 × 300 mm2 ROIcentered on the malformation in the cortical plate of E18.5 male fetal brains (n =6 for all groups). (C) Number of USVs emitted by P9 pups. Total USVs emittedduring test period (3 min) are plotted on the y axis [n = 16, 18, and 15 offspringfrom PBS-treated WT, RORgt HET, and RORgt TKO mothers, respectively; n =15, 11, and 28 from poly(I:C)-treated WT, RORgt HET, and RORgt TKO mothers,respectively; data from four to seven independent dams]. (D) Social approachbehavior is shown as a social preference index as in Fig. 3. [n = 21, 15, and 15

adult offspring from PBS-treated WT, RORgt HET, and RORgt TKO mothers,respectively; n = 36, 15, and 21 from poly(I:C)-treated WT, RORgt HET, andRORgt TKO mothers, respectively; data from four to seven independentdams]. (E) Marble-burying behavior as in Fig. 3 [n = 14, 19, and 15 adultoffspring from PBS-treated WT, RORgt HET, and RORgt TKO mothers,respectively; n = 32, 15, and 25 from poly(I:C)-treated WT, RORgt HET, andRORgt TKO mothers, respectively; data from four to seven independentdams]. (F) Total distance moved by offspring tested for social behavior. RORgtHET and RORgt TKO refer to RORgNeo/+; CD4-Cre/+ and RORgtFL/RORgNeo;CD4-Cre/+, respectively. (C) One-way ANOVA with Holm-Sidak post hoc tests.(B) and (D) Two-way ANOVA with Tukey’s post hoc tests. (E) and (F) One-way ANOVA with Tukey’s post hoc tests. ***P < 0.001, **P < 0.01, and *P <0.05. Means ± SEM.

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RORgt expression in maternal T cells isrequired for ASD-like phenotypes in theMIA offspring.As RORgt is a critical regulator of the IL-17apathway (13), we next investigated the role of ma-ternal RORgt in MIA-induced behavioral pheno-types in offspring. Note that TH17 cells and IL-17ahave been detected in the decidua, as well as inthe serum, during pregnancy in humans (33–35).CD45+ mononuclear cells, including CD4+ T cells,isolated from placenta and decidua of immune-activated WT mothers, but not from immune-activated mothers lacking both RORgt and theclosely related RORg isoform (RORg KO), pro-duced IL-17a upon ex vivo activation with PMAand ionomycin (fig. S6, A and B). Cells isolatedfrom WT and RORg KO mice secreted similaramounts of IFN-g, consistent with the specificeffect of RORgt on IL-17a expression (fig. S6C). Inline with this observation, poly(I:C) treatmentincreased placenta- and decidua-associated TH17,but not regulatory T, cells in pregnant dams, com-paredwith PBS treatment (fig. S6, D andE). RORgKOmice lack RORg and gt expression not only inCD4+ T cells but also in other lymphoid and non-immune system cells, and they have defectivedevelopment of secondary and tertiary lymphoidorgans (36, 37). To determine whether RORgtfunction specifically in T cells mediates MIA-induced phenotypes, we bred RORgtFL animals(fig. S7) to CD4-Cre mice to selectively inactivaterorc(t) in the T cells of pregnant mothers (RORgtTKO) (38). In these animals, the functions ofTH17 cells (CD4

+RORgt+ cells) and other RORgt-expressing abT cells are inhibited, but there is noeffect in RORgt-expressing innate (or innate-like) immune cells, including gdT, lymphoid tissue-inducer cells, and ILC3 cells (11, 12), as well as inRORg-expressing nonlymphoid cells. We foundthat RORgt TKO mothers failed to produce IL-17a even after poly(I:C) injection (fig. S6F). Notethat poly(I:C)-induced malformation of the cortexwas prevented in offspring from RORgt TKOmothers (Fig. 4, A and B), similar to the resultsfrom anti–IL-17a treatment (Fig. 2, B and D).Moreover, we found that prenatal exposure toMIA increased USV calls in pups derived fromWT or RORgt heterozygous (HET)mothers, butoffspring of RORgt TKO mothers had normalUSV behavior (Fig. 4C). T cell–specific deletion ofmaternal RORgt also abrogated the MIA-inducedsocial interaction deficit and excessive marbleburying in offspring (Fig. 4, D and E). These re-sults were not due to general activity defects inthe offspring ofWT, RORgt HET or TKOmothers(Fig. 4F). Because these offspring were derivedfrom mating RORgt WT, HET and TKO femalewith WT male mice, they all carried at least onecopy of functional RORgt. Therefore, the rescueof MIA-induced phenotypes observed in the off-spring of RORgt TKOmothers was not likely dueto the lack of TH17 cells in the offspring. Takentogether, these data indicate that maternal CD4+

T lymphocytes expressing RORgt (i.e., TH17 cells)are necessary for the MIA-mediated expressionof cortical abnormalities and three ASD-like be-haviors modeled in mouse offspring.

IL-17a administration to the fetal brainpromotes abnormal corticaldevelopment and ASD-likebehavioral phenotypesTo determine whether IL-17a acts on receptors inthe mother or the fetus to induce the MIA phe-notype, we injected poly(I:C) into IL-17Ra WT,HET, or KO mothers that had been bred toIL-17RaWT orHETmales (39). Removing one orboth copies of il17ra in the mother was sufficientto rescue the MIA-induced sociability deficit inoffspring, regardless of their genotypes (fig. S8A).Moreover, we found that reduced expression ofmaternal IL-17Ra in il17ra HET mothers led toreduced serum IL-17a in poly(I:C)-treatedmothers(fig. S8B). Thus, it is difficult, if not impossible, to

test the functional significance of the IL-17Ra inoffspring with a full germline il17ra KO withoutaffecting maternal TH17 cell activity. To circum-vent this problem, we asked if increasing IL-17Raactivity in the offspring, by introducing IL-17a di-rectly into the fetal brain in the absence of mater-nal inflammation, would be sufficient to induceMIA phenotypes. Injection of recombinant IL-17aprotein into the ventricles of the fetal brain atE14.5 in the absence of MIA (Fig. 5A) led to theappearance of disorganized cortical patches in asimilar location to those induced by MIA (Fig. 5,B to E). Unlike poly(I:C) injection, however, intra-ventricular injection of IL-17a resulted in thinnedcortical plates at the medial but not lateral partof the brain (fig. S9). This effect may reflect

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Fig. 5. IL-17a administration to the fetus promotes abnormal cortical development and ASD-likebehavioral phenotypes. (A) Schematic diagram of the experimental method. Each embryo was injectedintraventricularly at E14.5 with PBS or recombinant IL-17a protein mixed with Fastgreen dye. (B) SATB2and TBR1 staining in the cortex of E18.5 male fetal brains treated as in (A). Images are representative offive independent experiments. (C) Quantification of TBR1- and SATB2-positive cells in a 300-mm-wideROI corresponding to the region of the cortical plate containing the malformation in E18.5 male fetalbrain [n = 20 (PBS), n = 20 (IL-17a)]. (D) The spatial location of the disorganized cortical patch in E18.5fetal brain [n = 20 (IL-17a)]. (E) Percentage of the cortical patches in each category [n = 20 (IL-17a)].(F) USV assay, the number of pup calls [n = 15 (PBS), n = 17 (IL-17a); from five or six independent damsper treatment]. (G) Social approach behavior is shown as a social preference index as in Fig. 3 [n =12 (PBS), n = 18 (IL-17a); from five or six independent experiments]. (H) Marble-burying behavior. Per-centage of the number of buried marbles is plotted on the y axis [n = 12 (PBS), n = 18 (IL-17a); from fiveor six independent experiments]. (I) Total distance traveled during social approach test. (C) Two-wayANOVA with Tukey’s post hoc tests. (F), (H), and (I) Student's t tests. (G) One-way ANOVA with Tukey’spost hoc test. **P < 0.01; *P < 0.05; and ns, not significant. Means ± SEM.

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differences in the levels or types of inflammationassociated with poly(I:C) versus IL-17a injectionsor the time points at which poly(I:C) (E12.5) andIL-17a (E14.5) were administered. We also foundthat, compared with sham injection, IL-17a injec-tions led to an enhanced USV phenotype, socialapproach deficit, and increased marble-buryingbehavior, all similar in magnitude to those ob-served in MIA-exposed offspring (Fig. 5, F to H).These behavioral abnormalities were not due togroup differences in mobility (Fig. 5I). Neithercortical disorganization nor enhanced USV phe-notypes were observed after IL-17a injections intothe ventricles of IL-17Ra KO fetuses or upon IL-6injections into WT fetal brains (fig. S10, A to C),which suggests that IL-17a, but not IL-6, acts di-rectly in the fetal brain to induce these pheno-types. Of note, in agreementwith previous reports(7, 40), IL-6 injection into pregnant WT motherswas sufficient to produce MIA-associated behav-ioral (enhanced USV) and cortical phenotypes inthe offspring (fig. S10, D to F). Yet, pretreatmentof pregnant mothers with IL-17a–blocking anti-body prevented the phenotypes induced by ma-ternal IL-6 injection (fig. S10, D to F). Last, IL-17ainjection into brains of fetuses from poly(I:C)-injected IL-6 KOmothers was sufficient to elicitincreased pup USVs compared with PBS-injectedcontrols (fig. S10G). These data collectively dem-onstrate that activation of the IL-17Ra pathwayin the fetal brain, induced by intraventricularinjection of IL-17a into the fetus or by intraperi-toneal injection of poly(I:C) or IL-6 into pregnantmothers, results in MIA-associated phenotypesin the offspring.

Therapeutic treatment withIL-17a–blocking antibody in pregnantdams ameliorates MIA-associatedbehavioral abnormalitiesOur results suggest that pathological activationof the TH17 cell–IL-17a pathway during gestationin mothers with some inflammatory conditionsmay alter fetal brain development and contrib-ute to the ASD-like behavioral phenotypes in off-spring (fig. S11). TH17 cells require RORgt fortheir differentiation and exert their functionsby secreting multiple cytokines, including IL-17a. Abrogation of RORgt expression in maternalab T cells or blockade of the IL-17a pathway inpregnant dams resulted in the complete rescueof cortical developmental abnormalities and ASD-like behavioral phenotypes in offspring in theMIA rodent model. Thus, RORgt and TH17 cells(as well as their cytokines) may serve as goodtherapeutic targets to prevent the developmentof ASD phenotypes in the children of susceptiblemothers. To further test this idea, we adminis-tered IL-17a–blocking antibody to pregnantmice ina time window after MIA induction (Fig. 6A). Weinjected pregnant mothers with PBS or poly(I:C)at E12.5, followed by injection of IgG isotypecontrol or IL-17a–blocking antibody at E14.5, whenthe delayed expression of SABT2 manifests inMIA-exposed fetal brains (Fig. 2, A and C). Com-pared with PBS injection followed by controlantibody treatment, poly(I:C) injection followedby IL-17a–blocking antibody administrationpartially rescued USV andmarble-burying pheno-types (Fig. 6, B and D). However, MIA-inducedsocial interaction deficits were not corrected (Fig.

6C). These effects were not due to group differ-ences in mobility (Fig. 6E). Thus, treating preg-nant mothers with IL-17a–blocking antibody afterMIA can correct some of the ASD-like features,but pretreatment with this antibody may havegreater therapeutic potential.

ConclusionsOur results identify a specific maternal immunecell population that may have direct roles ininducing ASD-like phenotypes by acting on thedeveloping fetal brain. These findings raise thepossibility that modulation of the activity of acytokine receptor, IL-17Ra, in the central nervoussystem can influence neuronal development, withimplications as to specification of neuronal celltypes and their connectivity. Furthermore, notethat the loss of certain genes that induce ASD-likephenotypes were also found in mice with defectsin cortical lamination (41, 42). These observationsraise the possibility that some genetic and envi-ronmental factors that have roles in the etiologyof ASD function by way of similar physiolog-ical pathways. A related question is whether IL-17Ra signaling has a normal physiological functionin the fetal and adult brain, especially given thestructural similarities observed between the IL-17family cytokines and neurotrophin proteins (e.g.,nerve growth factor) (43, 44). Elucidating fur-ther downstream pathways of maternal IL-17a–producing T cells, both in MIA mothers andtheir offspring, will likely yield a better under-standing of the mechanisms by which inflam-mation in utero contributes to the developmentof neurodevelopmental disorders, such as ASD,

938 26 FEBRUARY 2016 • VOL 351 ISSUE 6276 sciencemag.org SCIENCE

Fig. 6. Therapeuticeffects of blockingIL-17a signaling inpregnant dams. (A)Schematic diagram ofthe experimentaldesign. At E12.5, preg-nant mothers wereinjectedwithPBSor poly(I:C) to induce MIA.Twodays later (E14.5), thepregnant mothers weretreated with isotype oranti–IL-17a. At P7 to~P9, pups wereseparated from themothers to measureUSVcalls. At ~8 weeks,male offspring weresubjected to the socialapproach test andmarble-burying test.(B) USV assay. Thenumber of pup calls isplotted on the y axis {n=17 (PBS,Cont); n= 17 [poly(I:C),Cont]; n= 27 [poly(I:C), anti–IL-17a]; from three or four independent dams per treatment}. (C) Social approach behavior is shown asa social preference index (Fig. 3) {n = 12 (PBS,Cont), n = 10 [poly(I:C), Cont], n = 17 [poly(I:C), anti–IL-17a]; from three or four independent dams per treatment}.(D) Marble-burying behavior as in Fig. 3 {n = 12 (PBS, Cont), n = 10 [poly(I:C), Cont], n = 17 [poly(I:C), anti–IL-17a]; from three or four independent dams pertreatment}. (E) Total distance traveled during social approach behavior. (B), (D), and (E) One-way ANOVA with Tukey’s post hoc tests. (C) Two-way ANOVAwith Tukey’s post hoc test. **P < 0.01 and *P < 0.05. Means ± SEM.

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and, additionally, may provide insights into theroles of cytokine receptors in the central nerv-ous system.

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(2006).6. B. K. Lee et al., Brain Behav. Immun. 44, 100–105 (2015).7. S. E. P. Smith, J. Li, K. Garbett, K. Mirnics, P. H. Patterson,

J. Neurosci. 27, 10695–10702 (2007).8. N. V. Malkova, C. Z. Yu, E. Y. Hsiao, M. J. Moore,

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9. C. M. Wilke, K. Bishop, D. Fox, W. Zou, Trends Immunol. 32,603–611 (2011).

10. N. Manel, D. Unutmaz, D. R. Littman, Nat. Immunol. 9, 641–649(2008).

11. H. Spits, J. P. Di Santo, Nat. Immunol. 12, 21–27 (2011).12. M. Lochner et al., J. Exp. Med. 205, 1381–1393 (2008).13. I. I. Ivanov et al., Cell 126, 1121–1133 (2006).14. L. Y. Al-Ayadhi, G. A. Mostafa, J. Neuroinflammation 9, 158

(2012).15. K. Suzuki et al., PLOS ONE 6, e20470 (2011).16. B. van der Zwaag et al., PLOS ONE 4, e5324 (2009).17. M. Mandal, A. C. Marzouk, R. Donnelly, N. M. Ponzio, J. Reprod.

Immunol. 87, 97–100 (2010).18. E. Y. Hsiao, S. W. McBride, J. Chow, S. K. Mazmanian,

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26–40 (2011).

ACKNOWLEDGMENTS

We thank E. Kurz, D. Montgomery, and Y. Cai for assistance withexperiments and J. Koll for providing the il17raKO mouse line, whichwas originally developed by Amgen. The il17raKO line will beavailable from D.R.L. under a material transfer agreement withAmgen. We also thank M. Sellars for critical reading of themanuscript. The data presented in this paper are tabulated in the

main text and in the supplementary materials. This work wassupported by the Simons Foundation Autism Research Initiative(D.R.L.); the Simons Foundation to the Simons Center for theSocial Brain at Massachusetts Institute of Technology (Y.S.Y.and G.B.C.); Robert Buxton (G.B.C.); the National ResearchFoundation of Korea grants MEST-35B-2011-1-E00012 (S.K.); andNRF-2014R1A1A1006089 (H.K.); the Crohn’s and Colitis Foundationof America grant 329388 (S.V.K.); the Smith Family Foundation(J.R.H.); the Searle Scholars Program (J.R.H.); Alzheimer’sAssociation MNIRGDP-12-258900 (C.A.H.); Brain and BehaviorResearch Foundation (NARSAD) 21069 (C.A.H.); and NIH grantsF31NS083277 (H.W.), R00DK091508 (J.R.H.), and R01NS086933(C.A.H.); and the Howard Hughes Medical Institute (D.R.L.). D.R.L.

and J.R.H. are inventors on a patent application filed by New YorkUniversity, related to the studies reported here.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/351/6276/933/suppl/DC1Materials and MethodsSupplementary TextFigs. S1 to S11References (45–47)

17 July 2015; accepted 14 January 2016Published online 28 January 201610.1126/science.aad0314

MEIOSIS

A DNA topoisomerase VI–likecomplex initiatesmeiotic recombinationNathalie Vrielynck,1 Aurélie Chambon,1 Daniel Vezon,1 Lucie Pereira,1 Liudmila Chelysheva,1

Arnaud DeMuyt,1* Christine Mézard,1 Claudine Mayer,2,3,4 Mathilde Grelon1†

The SPO11 protein catalyzes the formation of meiotic DNA double strand breaks (DSBs) andis homologous to theAsubunit ofanarchaeal topoisomerase (topoVI).TopoVI areheterotetramericenzymes comprising two A and two B subunits; however, no topo VIB involved in meioticrecombination had been identified.We characterized a structural homolog of the archaeal topoVIB subunit [meiotic topoisomerase VIB–like (MTOPVIB)], which is essential for meiotic DSBformation. It formsacomplexwith the twoArabidopsis thalianaSPO11orthologs required formeioticDSB formation (SPO11-1 and SPO11-2) and is absolutely required for the formation of theSPO11-1/SPO11-2 heterodimer.These findings suggest that the catalytic core complex responsiblefor meiotic DSB formation in eukaryotes adopts a topo VI–like structure.

Meiotic recombination is the key step insexual reproduction leading to the pro-duction of haploid gametes and is there-fore essential for the fertility of mosteukaryotes. It is initiated by the induc-

tion of DNA double strand breaks (DSBs), whichare catalyzed by the evolutionarily conservedSPO11 protein (1). SPO11 shows sequence sim-ilarities to the A subunit of the archaeal type IIDNA topoisomerase, topoisomerase VI (topo VI)(2). Topo VI enzymes relax DNA supercoils bycutting both DNA strands of a DNA helix in anadenosine 5′-triphosphate (ATP)–dependent man-ner, forcing the passage of another DNA duplexthrough the generated break and eventually rel-igating the break, regenerating an intact DNAmolecule (3). Topo VI enzymes are active asheterotetramers, composed of two A and two Bsubunits. The two topo VIA subunits carry thecatalytically active tyrosines and associate as adimer to form the catalytic core of the topo VIenzyme (2). The topo VIB subunits contain an

ATP-binding domain known as the Bergerat fold,which is characteristic of the GHKL (Gyrase,HSP90, histidine kinase,MutL) superfamily (2, 4).Topo VIB also possess a C-terminal transducerdomain that transfers the conformational changesinduced by ATP binding and hydrolysis from theGHKL to the catalytic A subunits (5). On the basisof the similarity between SPO11 and topoVIA, andbecause SPO11 can be purified covalently associ-ated with the meiotic DSB ends (6), it was pro-posed that at the onset ofmeiotic recombination,SPO11 dimerizes to form the catalytic core respon-sible for DNA DSB formation. In Arabidopsisthaliana, genetic analyses revealed that two non-redundant SPO11 homologs (SPO11-1 and SPO11-2) are absolutely required forDSB formation (7–9),suggesting that meiotic DSBs are catalyzed by aSPO11-1/SPO11-2 heterodimer rather than a homo-dimer. Although most eukaryotic lineages possessat least one SPO11 protein, until now no topo VIBhomolog involved in meiotic recombination hadbeen identified. Here, we present the first charac-terization of a structural homolog of the archaealtopo VIB subunit required formeiotic DSB forma-tion. We show that it mediates the formation ofthe SPO11-1/SPO11-2 heterodimer, changing ourview of the nature of the core complex involved inmeiotic DSB formation.In a screen for A. thaliana mutants with re-

duced fertility, we identified two allelic lines,

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1Institut Jean-Pierre Bourgin (IJPB), INRA, AgroParisTech,CNRS, Université Paris-Saclay, RD10, 78026 Versailles Cedex,France. 2Institut Pasteur, 25 rue du Dr Roux, 75015, Paris,France. 3CNRS, UMR 3528, 75724 Paris cedex 15, France.4Université Paris Diderot, Sorbonne Paris Cité, Paris, France.*Present address: Institut Curie, PSL Research University, CNRS,UMR3664, F-75005, Paris, France. †Corresponding author. E-mail:mathilde.grelon@versailles.inra.fr

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The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring

and Jun R. HuhGloria B. Choi, Yeong S. Yim, Helen Wong, Sangdoo Kim, Hyunju Kim, Sangwon V. Kim, Charles A. Hoeffer, Dan R. Littman

originally published online January 28, 2016DOI: 10.1126/science.aad0314 (6276), 933-939.351Science 

, this issue p. 933; see also p. 919Scienceof interleukin-17a during gestation reduced ASD symptoms in offspring.interleukin-17a in the mothers caused cortical defects and associated ASD behaviors in offspring. Therapeutic targetingreminiscent of ASD (see the Perspective by Estes and McAllister). A subset of T helper cells that make the cytokine

provided infectious or inflammatory stimuli to pregnant mice, which resulted in of spring exhibiting behaviorset al.immune system during pregnancy, especially during key early periods of fetal neurodevelopment, may play a role. Choi

The causes of autism spectrum disorder (ASD) are complex and not entirely clear. Alterations in the mother'sA T cell cause for autism?

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MATERIALSSUPPLEMENTARY http://science.sciencemag.org/content/suppl/2016/01/27/science.aad0314.DC1

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