The Intellectual Disability Risk GeneKdm5bRegulates Long-Term Memory Consolidation in the Hippocampus

Abstract

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants inKDM5Bare 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 aKdm5bΔARIDallele that lacks demethylase activity.Kdm5bΔARID/ΔARIDmice 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 theKdm5bΔARID/ΔARIDhippocampus. Next, we knocked downKdm5bspecifically in the adult, WT mouse hippocampus with shRNA.Kdm5bknockdown 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 withKDM5Bgene variants are caused by direct effects on memory consolidation mechanisms.