Desipramine reverses remote memory deficits by activating calmodulin-CaMKII pathway in aUTXknockout mouse model of Kabuki syndrome

Abstract

BackgroundKabuki 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 ofUTXin cognitive function remains unclear. Currently, no targeted therapies are available for KS.AimsThis study aimed to investigate howUTXregulates cognition, to explore the mechanisms underlyingUTXdysfunction and to identify potential molecular targets for treatment.MethodsWe generatedUTXconditional knockout mice and found thatUTXdeletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation.ResultsUTX-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.ConclusionsOur results reveal an epigenetic mechanism underlying the important role ofUTXin synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS.