期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23987-z
关键词
-
资金
- NIH [R01MH095147]
- Believe in a Cure, Inc.
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Cell Science Research Foundation
- Takeda Science Foundation
- Brain Science Foundation
- [JP17H05775]
- [JP17K07102]
- [JP19H04789]
- [JP19H05228]
- [JP20K07362]
- [JP15H01667]
- [JP19H03343]
- [JP20H05481]
- [JP20H05916]
This study reveals that FoxG1 regulates the formation of cortical GABAergic circuits affecting social behavior during a specific postnatal time window in mouse models of ASD. The second postnatal week is a critical period to prevent ASD-like social impairments. Transplantation of GABAergic precursor cells or modulation of GABAergic tone can respectively ameliorate or exacerbate circuit functionality and social behavioral defects.
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. Cortical excitatory/inhibitory (E/I) imbalance is a feature of autism spectrum disorder (ASD). Here, the authors show that FoxG1 regulates the formation of cortical GABAergic circuits affecting social behaviour during a specific postnatal time window in mouse models of ASD.
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