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

Abstract

Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD). ASD is caused by genetic and environmental factors. Several genes have been associated with syndromic forms of ASD, including FOXG1. However, when and how dysregulation of FOXG1 can result in defects in inhibitory circuit development and ASD-like social impairments is unclear. Here, we show that increased or decreased FoxG1 expression in both excitatory and inhibitory neurons results in ASD-related circuit and social behavior deficits in our mouse models. We observe that the second postnatal week is the critical period when regulation of FoxG1 expression is required to prevent subsequent ASD-like social impairments. Transplantation of GABAergic precursor cells prior to this critical period and reduction in GABAergic tone via Gad2 mutation ameliorates and exacerbates circuit functionality and social behavioral defects, respectively. Our results provide mechanistic insight into the developmental timing of inhibitory circuit formation underlying ASD-like phenotypes in mouse models.

Behavioral and imaging analysis of Foxg1 heterozygous mice

“…Consistent with published work(14), we found decreased interest to a novel mouse in the 3-Chamber test, however in contrast we found increased rather than decreased sociability in the same task (Table 3). These experiments were conducted at different ages and future longitudinal studies will be needed to determine if this social interaction difference is age related or a function of different Foxg1 alleles or background strains.…”

“…While both studies were conducted at roughly the same age, the caveats regarding specific allele and strain mentioned above remain. A recent study identified deficits in working memory using the 8-arm radial maze in a different allele of Foxg1 (14). Together these results across different Consistent with published work (14), we found decreased interest to a novel mouse in the 3-Chamber test, however in contrast we found increased rather than decreased sociability in the same task (Table 3).…”

“…Encouragingly, recent work demonstrated that early life transplantation of GABAergic neuronal precursors could improve some phenotypes (14).…”

“…Additionally, neurophysiological experiments have found alterations in EEG power spectral features (14) and visual evoked potentials (17). Here we present the generation and initial characterization of a new mouse model of FS, which was generated by the insertion of a loxPflanked "STOP" cassette containing a splice acceptor to disrupt translation of the FoxG1 protein.…”

Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors

“…Loss of Foxg1 leads to defective social interaction and impaired spatial learning and memory [12,16]. A concomitant misregulation of Foxg1 in postnatal, gabaergic and glutamatergic neurons, is necessary and sufficient to trigger autism spectrum disorder-like (ASD-like) phenotypes [17].…”