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

Goichi Miyoshi (), Yoshifumi Ueta, Akiyo Natsubori, Kou Hiraga, Hironobu Osaki, Yuki Yagasaki, Yusuke Kishi, Yuchio Yanagawa, Gord Fishell, Robert P. Machold and Mariko Miyata
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Goichi Miyoshi: Tokyo Women’s Medical University
Yoshifumi Ueta: Tokyo Women’s Medical University
Akiyo Natsubori: Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science
Kou Hiraga: Tokyo Women’s Medical University
Hironobu Osaki: Tokyo Women’s Medical University
Yuki Yagasaki: Tokyo Women’s Medical University
Yusuke Kishi: Graduate School of Pharmaceutical Sciences, University of Tokyo
Yuchio Yanagawa: Gunma University Graduate School of Medicine
Gord Fishell: NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine
Robert P. Machold: NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine
Mariko Miyata: Tokyo Women’s Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23987-z

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