The Histone H3K27 Demethylase UTX Regulates Synaptic Plasticity and Cognitive Behaviors in Mice

Abstract

Histone demethylase UTX mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish a mechanistic switch to activate large sets of genes. Mutation of <i>Utx</i> has recently been shown to be associated with Kabuki syndrome, a rare congenital anomaly syndrome with dementia. However, its biological function in the brain is largely unknown. Here, we observe that deletion of <i>Utx</i> results in increased anxiety-like behaviors and impaired spatial learning and memory in mice. Loss of <i>Utx</i> in the hippocampus leads to reduced long-term potentiation and amplitude of miniature excitatory postsynaptic current, aberrant dendrite development and defective synapse formation. Transcriptional profiling reveals that <i>Utx</i> regulates a subset of genes that are involved in the regulation of dendritic morphology, synaptic transmission, and cognition. Specifically, <i>Utx</i> deletion disrupts expression of neurotransmitter 5-hydroxytryptamine receptor 5B (<i>Htr5b</i>). Restoration of <i>Htr5b</i> expression in newborn hippocampal neurons rescues the defects of neuronal morphology by <i>Utx</i> ablation. Therefore, we provide evidence that <i>Utx</i> plays a critical role in modulating synaptic transmission and cognitive behaviors. <i>Utx</i> cKO mouse models like ours provide a valuable means to study the underlying mechanisms of the etiology of Kabuki syndrome.