The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

The histone lysine demethylase KDM5B has been implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the normal adult population. To help distinguish between developmental and demethylase-dependent functions of KDM5B in hippocampus-dependent learning and memory, we studied mice homozygous for a Kdm5bDARID allele that lacks demethylase activity. Demethylase-deficient Kdm5bDARID/DARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in mice in the home cage (baseline) and hyperactivated upon learning stimulus compared to wildtype mice. The expression of other learning-associated genes was also significantly altered in the Kdm5bDARID/DARID hippocampus. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on learning and memory mechanisms. Total RNA was extracted using Trizol Reagent. RNA was next purified with the Monarch total RNA miniprep kit (New England Biolabs). Hippocampal mRNA profiles of WT and Kdm5bDARID/DARID mice at different timepoints (baseline and 1h and 3h post fear conditioning) were generated by sequencing on the Illumina Nextseq 6000.组蛋白赖氨酸去甲基化酶KDM5B（histone lysine demethylase KDM5B）已被证实与隐性智力障碍相关，且KDM5B的杂合蛋白截短变异与正常成年人群的认知功能降低有关。为区分KDM5B在海马依赖型学习记忆中的发育依赖功能与去甲基化依赖功能，我们针对携带缺失去甲基化活性的Kdm5bDARID等位基因的纯合小鼠开展了研究。去甲基化缺陷型Kdm5bDARID/DARID小鼠在海马依赖型学习任务中表现出活动过度与长期记忆缺陷。与野生型（wildtype, WT）小鼠相比，居家笼饲养状态（基线水平）下的即刻早期活性依赖基因表达在该小鼠中被下调，而在受到学习刺激后则呈现过度激活。其余与学习相关的基因在Kdm5bDARID/DARID小鼠的海马体中也出现了显著表达改变。上述研究结果表明，KDM5B是成年海马体中基因表达与突触可塑性的关键调控因子，同时提示与KDM5B基因变异相关的部分认知表型，是由学习记忆机制的直接异常所导致。总RNA采用Trizol试剂提取，随后使用Monarch总RNA小量制备试剂盒（New England Biolabs）进行纯化。我们通过Illumina Nextseq 6000测序平台，获取了野生型与Kdm5bDARID/DARID小鼠在不同时间点（基线状态、恐惧条件反射后1小时与3小时）的海马体mRNA表达谱。