The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b^ARID allele that lacks demethylase activity. Kdm5b^ARID/ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b^ARID/ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. 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 memory consolidation mechanisms.

组蛋白赖氨酸脱甲基酶 KDM5B 与隐性智力障碍有关，KDM5B中的杂合蛋白质截短变体与人群认知功能下降有关。 KDM5 赖氨酸脱甲基酶家族在大脑中具有发育和稳态功能，其中一些功能似乎独立于赖氨酸脱甲基酶活性。为了确定 KDM5B 在海马依赖性学习和记忆中的功能，我们首先研究了Kdm5b纯合子的雄性和雌性小鼠^ARID等位基因缺乏去甲基化酶活性。 Kdm5b^干旱/ARID小鼠在海马依赖性学习任务中表现出多动症和长期记忆缺陷。与野生型（WT）小鼠相比，这些小鼠中立即早期活动依赖性基因的表达下调，并且在学习刺激后过度激活。许多其他与学习相关的基因在Kdm5b中也显着失调。^{干旱/干旱的}海马体。接下来，我们用 shRNA 特异性敲除成年 WT 小鼠海马体中的Kdm5b 。 Kdm5b敲低会导致自发性癫痫发作、多动症以及海马依赖性长期记忆和长期增强缺陷。这些发现确定 KDM5B 是成人海马体基因表达和突触可塑性的关键调节因子，并表明至少一些与KDM5B基因变异相关的认知表型是由对记忆巩固机制的直接影响引起的。