Fig. 2: ASD FOXG1 syndrome social phenotypes are due to neuronal FoxG1 haploinsufficiency, but not microcephaly or loss of GABAergic cells. | Nature Communications

Fig. 2: ASD FOXG1 syndrome social phenotypes are due to neuronal FoxG1 haploinsufficiency, but not microcephaly or loss of GABAergic cells.

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

Fig. 2

a, b Consistent with the microcephaly phenotypes found in human FOXG1 haploinsufficiency patients, Heterozygous animals (b) exhibit a smaller brain size and reduced GABAergic cell numbers (labeled by Dlx5a-Cre; Ai9) compared to wild type (a). Blue brackets indicate the thickness of the barrel cortex in wild type animals. c In the neuronal FoxG1 Heterozygous model, FoxG1 haploinsufficiency only takes place in postmitotic neurons, thus sparing the progenitors and glia of the neocortex. d–i In situ hybridization with a Gad1 antisense probe (black) labels GABAergic cell populations, with DAPI stain (blue) to visualize the laminar structure of the cortex in Control (d, e), FoxG1 Heterozygous (f, g) and the postmitotic neuronal Heterozygous model (h, i: Nex-Cre; Dlx-Cre; FoxG1-C/ +, scheme in l). In the Heterozygous model, the cortical thickness of the S1 Barrel (g) but not the mPFC (f) is reduced compared to the Control (d, e). Removal of one copy of FoxG1 selectively in postmitotic neuronal populations rescues the Heterozygous microcephaly phenotype (h–j). While GABAergic cell density is reduced in both the mPFC and S1 Barrel cortex of the Heterozygous model (f, g) compared to the Control (d, e), this phenotype was completely rescued in Neuronal Het animals (h, i, k). j, k The thickness of cortical layers 1–6 (j) as well as Gad1-positive cell density (k) were analyzed. Control: n = 4, FoxG1 Het: n = 6(mPFC) or 4(S1BF), Neuronal Het: n = 4, Control vs. Het: p = 0.0945 (j: mPFC), =0.00398**(j: S1), = 0.0377* (k: mPFC), = 0.0276*(k: S1), Control vs. Neuronal Het: p = 0.909, = 0.101, = 0.613, = 0.463 (same order with Het). l, m Genetic strategy (l) and results from three-chamber social interaction experiments of FoxG1 Low model (m). For the sake of clarity, in the bar graphs (m), the first 10 min of habituation data is not included (see the full data sets in Supplementary Fig. 1). m Neuronal Het animals without any microcephaly or GABAergic cell loss phenotypes showed ASD-like social behavioral impairments similar to the Heterozygous model (Fig. 1a–c). This was not the case in either Glu Low or GABA Low models and unexpectedly, GABA Low models showed a strong preference for the social side of the chamber (orange asterisks) during the social novelty session. Data are mean ± SEM, p values are from two-tailed t-test.

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