KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [snRNA-seq]

Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose mutations cause KAT6A Syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2, encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Importantly, deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A Syndrome and related neurodevelopmental diseases. Nuclei mRNA profiles in hippocampal tissues of adult Kat6a-f/f and NEX-cre, Kat6a-f/f (Kat6a-cKO) mice were generated by snRNA-seq, using Illumina NovaSeq 6000智力障碍（Intellectual Disability, ID）影响约2%的人群，ID相关基因富集于表观遗传因子编码基因，其中涵盖最大的组蛋白赖氨酸乙酰转移酶家族（KAT5-KAT8）。该家族成员KAT6A的突变可引发KAT6A综合征，智力障碍为其常见临床特征，但其潜在分子机制至今尚未阐明。本研究发现，KAT6A缺失会损伤小鼠海马CA3区的突触结构与突触可塑性，却不影响CA1区，最终导致小鼠出现记忆缺陷。我们进一步鉴定出一种在CA3区富集的基因Rspo2，其编码Wnt激活因子R-spondin 2，是KAT6A的关键转录靶标。尤为关键的是，在兴奋性神经元中敲除Rspo2会损害记忆形成过程；而在CA3区恢复RSPO2的表达，能够挽救Kat6a突变小鼠的Wnt信号通路缺陷与学习相关行为异常。综上，本研究结果证实KAT6A-RSPO2-Wnt信号通路在调控海马CA3区突触可塑性与认知功能中发挥关键作用，为KAT6A综合征及相关神经发育疾病提供了潜在治疗靶点。本研究通过单细胞核RNA测序（single nuclear RNA sequencing, snRNA-seq）技术，使用Illumina NovaSeq 6000平台，获取了成年Kat6a-f/f与NEX-cre, Kat6a-f/f（Kat6a条件性敲除，Kat6a-cKO）小鼠的海马组织细胞核mRNA表达谱。