Fig. 6: Normalization of the mPFC E/I balance by incrementing GABAergic tone during the critical period ameliorates social phenotypes in the FoxG1 ASD model. | Nature Communications

Fig. 6: Normalization of the mPFC E/I balance by incrementing GABAergic tone during the critical period ameliorates social phenotypes in the FoxG1 ASD model.

From: FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes

Fig. 6

a Donor GABAergic cell precursors were dissected out from the MGE (medial ganglionic eminence, arrowhead) of E13.5 embryos and dissociated. Subsequently, donor cells were bilaterally transplanted into the mPFC (medial prefrontal cortex) of 1 week old FoxG1 Heterozygous or Wild Type animals. The E/I balance of layer 2/3 pyramidal cells was analyzed at 2 weeks (DIC image) and the social behavioral assay was carried out at 6 weeks. b A representative example of cell-transplanted mPFC slices after the E/I analysis at 2 weeks. A biocytin-filled pyramidal cell and EGFP-labeled GABAergic cell transplants are shown. Control wild type and the Heterozygous animals maintained a similar density of transplanted cells within the adult mPFC (Supplementary Fig. 7b–d). c–f E/I balance data for frequency and peak amplitude values at 2 weeks (c, d, n = 16) and in adults (e, f, n = 22). Cell-transplanted Heterozygotes showed comparable E/I ratios to the control Wild Type animals (NS in orange) for both frequency (p = 0.424) and amplitude (p = 0.148) at 2 weeks and in adulthood (p = 0.379 and 0.828). p = 8.04 × 10−8****, 7.47 × 10−8**** (c, mEPSC and mIPSC), = 0.0438*, 0.00294**(d), = 0.291, 0.115 (e),  = 8.69 × 10−8****, 2.95 × 10−7**** (f). g–j Upon receiving GABAergic cell precursors at 1 week (g, h, left scheme), social behaviors of Wild Type (n = 34) and Hets (n = 29) were analyzed by three-chamber assay (g, h). In addition, in order to test the importance of rebalancing E/I ratio of the Hets during the critical period (1–2 weeks), cell transplantation was carried out at postnatal 3 weeks (i, n = 21). Time spent in the social side of the chamber during sociability sessions (NS in orange, p = 0.202) and center chamber during social novelty sessions (NS in orange, p = 0.222) were comparable between the 1 week-transplanted Wild Type and Heterozygotes (j). p = 4.48 × 10−7****, 1.32 × 10−6****, 0.0877, 0.00126**, 0.00264**, 0.275 (j, left vs right, from left to right). k The impaired sociability score in the Heterozygotes is ameliorated (p = 0.122) and exacerbated in the GABAergic cell precursor transplantation and Gad2 mutation models, respectively. l In contrast to social behavior (j, k), working memory deficits of the Heterozygotes were not ameliorated upon GABAergic cell transplantation into the mPFC (n = 54, p = 0.698). Data are mean ± SEM, p values are from two-tailed t-test. Scale bars: 1 mm (a, left), 20 µm (a, right), 100 µm (b).

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