Desipramine reverses remote memory deficits by activating calmodulin-CaMKII pathway in a UTX knockout mouse model of Kabuki syndrome.

Abstract

Background: Kabuki syndrome (KS) is a rare developmental disorder characterised by multiple congenital anomalies and intellectual disability. UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), which encodes a histone demethylase, is one of the two major pathogenic risk genes for KS. Although intellectual disability is a key phenotype of KS, the role of UTX in cognitive function remains unclear. Currently, no targeted therapies are available for KS.

Aims: This study aimed to investigate how UTX regulates cognition, to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment.

Methods: We generated UTX conditional knockout mice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation.

Results: UTX-knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, impaired long-term potentiation and deficit in remote contextual fear memory. These effects were reversed by an Food and Drug Administration-approved drug desipramine.

Conclusions: Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS.