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.
Highlights
Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD)
We show that the GABAergic system plays pivotal roles during the critical period by demonstrating that weakening or supplementing cortical GABAergic tone exacerbates or ameliorates the social behavioral impairments of the FoxG1 ASD model, respectively
In order to address the developmental circuit mechanisms underlying the social behavioral alterations found in ASD patients, we first examined if ASD FOXG1 syndrome could be recapitulated in rodents to model the disease phenotypes
Summary
Abnormalities in GABAergic inhibitory circuits have been implicated in the aetiology of autism spectrum disorder (ASD). Recent advances in sequencing techniques have revealed FOXG1 point-mutations in idiopathic ASD children (FOXG1 Research Foundation), suggesting that there are more undiscovered FOXG1 syndrome patients world-wide Both when during development and in which brain circuits FOXG1 dysregulation contributes to ASD etiology have not been elucidated. We show that the GABAergic system plays pivotal roles during the critical period by demonstrating that weakening or supplementing cortical GABAergic tone exacerbates or ameliorates the social behavioral impairments of the FoxG1 ASD model, respectively. We identify both the critical time-window and inhibitory circuit mechanisms that lead to ASD-related social behavioral impairments upon FoxG1 dysregulation. Our results support the promise of therapeutic approaches to ameliorate ASD phenotypes through the early intervention of cortical GABAergic systems
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
