Laboratory of Behavioral Neuroscience, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nat Commun. 2024 Jun 12;15(1):4531. doi: 10.1038/s41467-024-48430-x.
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.
自闭症谱系障碍（ASD）个体存在更高的社交记忆损伤发生率。我们之前的一系列研究表明，海马腹侧 CA1 区（vCA1）神经元具有社交记忆印痕，而在 ASD 相关的 Shank3 敲除小鼠中，vCA1 神经元中社交记忆的神经生理表现被破坏。然而，Shank3 在 vCA1 中的功能障碍是否导致 ASD 中观察到的社交记忆损伤仍不清楚。在这项研究中，我们发现通过腺相关病毒（AAV）或专门的细胞外囊泡（EV）介导的体内基因编辑特异性敲除 vCA1 中的 Shank3（vCA1-Shank3 cKO）足以重现雄性小鼠的社交记忆损伤。此外，利用 EV 介导的 Shank3-cKO，我们能够定量研究 Shank3 在社交记忆中的作用。我们的结果表明，Shank3-cKO 神经元的比例需要达到一定的阈值，才能破坏社交记忆。因此，我们的研究为 vCA1 中的社交记忆群体编码以及 ASD 中社交记忆损伤的病理机制提供了深入的了解。
