孤独症模型Shank3B敲除小鼠海马CA1对空间和社交信息的编码

孤独症谱系障碍是一种常见的神经发育类疾病，其在中国的发病率约为0.7%，该疾病的社交障碍、感觉异常等症状给患者、家属以及社会带来许多不便，然而人们对该疾病的认识仍然不够深入。已有研究表明，Shank3等基因突变是导致该疾病的原因之一，但基因突变引起的突触功能异常如何对行为产生影响尚未完全阐明。另一方面，孤独症患者在社交和语言之外的其他能力，例如空间导航是否也受到了影响仍然未能确定。

因此我们利用Shank3B纯合敲除（Shank3B^-/-）小鼠作为孤独症谱系障碍的模型，在小鼠奔跑于虚拟线性轨道时记录其海马CA1的神经元活动，并与野生型小鼠进行对比。结果显示，在熟悉环境中，Shank3B^-/-小鼠的CA1神经元能形成稳定的位置场，但相较野生型小鼠，其钙事件频率和空间信息率更高，位置细胞的比例也更高。在陌生环境中，Shank3B^-/-小鼠的CA1神经元同样能编码空间信息，并能通过重映射区分不同环境，但空间信息率和位置细胞的比例较野生型小鼠更低。在存在社交刺激的空间导航范式中，社交刺激使野生型和Shank3B^-/-小鼠的CA1神经元的空间信息率下降，但相较野生型小鼠，社交刺激对Shank3B^-/-小鼠CA1神经元的空间编码稳定性影响较小。

综上所述，通过对海马CA1兴奋性神经元进行在体钙成像，并对比野生型和Shank3B^-/-小鼠的神经元活动，我们发现：Shank3B^-/-小鼠的CA1神经元具有更高的钙事件频率，在熟悉环境中具有更高的空间编码能力，在陌生环境中相反，并且对社交刺激不敏感。这些结果提示Shank3基因突变可能使海马CA1兴奋性神经元具有更高的兴奋性，使空间导航能力发生改变。

Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition with a prevalence of approximately 0.7% in China. The disorder's social and sensory symptoms cause significant challenges for individuals, families, and society, yet understanding of ASD remains limited. While prior research has implicated gene mutations like Shank3 as contributing factors, the exact impact of synaptic dysfunction resulting from these mutations on behavior remains elusive. Additionally, it's unclear whether ASD affects abilities beyond social and language domains, such as spatial navigation.

Therefore, we used Shank3B homozygous knockout (Shank3B^-/-) mice as a model of ASD. Using in vivo calcium imaging of hippocampal CA1 excitatory neurons, we observed their activity as mice traversed a virtual linear track, comparing them with wild-type mice. Findings revealed that in familiar environment, Shank3B^-/- mice's CA1 neurons could form stable place fields, but compared to wild-type mice, they exhibited higher calcium event rate and spatial information, as well as a higher proportion of place cells. In novel environment, CA1 neurons of Shank3B^-/- mice could also encode space and distinguish different environments by remapping, but the spatial information and proportion of place cells were lower compared to wild-type mice. In the spatial navigation paradigm involving social stimuli, social stimuli led to a decreasing spatial information of CA1 neurons in both wild-type and Shank3B^-/- mice, but the effect of social stimuli on the spatial coding stability of CA1 neurons in Shank3B^-/- mice was smaller compared to wild-type mice.

In summary, through in vivo calcium imaging of hippocampal CA1 excitatory neurons and comparison of neuronal activity between wild-type and Shank3B^-/- mice, we found that CA1 neurons of Shank3B^-/- mice exhibited higher calcium event rate, higher spatial coding ability in familiar environments, lower spatial coding ability in novel environments, and insensitivity to social stimuli. These results suggest that Shank3 gene mutation may lead to increased excitability of hippocampal CA1 excitatory neurons, resulting in alterations in spatial navigation abilities.

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