Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice

Myung Chung, Katsutoshi Imanaka, Ziyan Huang, Akiyuki Watarai, Mu-Yun Wang, Kentaro Tao, Hirotaka Ejima, Tomomi Aida, Guoping Feng and Teruhiro Okuyama ()
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Myung Chung: The University of Tokyo
Katsutoshi Imanaka: The University of Tokyo
Ziyan Huang: The University of Tokyo
Akiyuki Watarai: The University of Tokyo
Mu-Yun Wang: The University of Tokyo
Kentaro Tao: The University of Tokyo
Hirotaka Ejima: The University of Tokyo
Tomomi Aida: Massachusetts Institute of Technology
Guoping Feng: Massachusetts Institute of Technology
Teruhiro Okuyama: The University of Tokyo

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

Date: 2024
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DOI: 10.1038/s41467-024-48430-x

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