CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression

Yongqing Liu,Shaoyi Li,Zhuo Huang,Fei Pei,Ming Yi,Wei Ke,Weining Ma,Yu Zhang,Yongfeng Shang,Shumeng Liu,Chan Zhang,Yousheng Shu,Shirong Lai,Jing Liang

doi:10.1038/s41467-017-00368-z

Abstract

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. However, how intrinsic excitability is regulated is still not fully understood. Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL exhibit higher neuronal threshold and are less prone to epileptogenesis. Finally, examination of human brain tissues reveals decreased CDYL and increased SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience-dependent gene regulation in controlling intrinsic excitability.

Highlights

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy
We demonstrated that Chromodomain Y-like (CDYL) transcriptionally represses SCN8A, the gene encoding Nav1.6 sodium channels, such that the axonal Nav1.6 currents were reduced
Given that dysfunction of Nav1.6 currents is involved in altered learning, memory, and many neurological and psychiatric brain disorders, such as epilepsy, intellectual disability and pain[34, 36, 37, 44], our results suggest that modulating neuronal intrinsic excitability via the CDYL–SCN8A axis could play a key role in both physiological and pathological processes of the brain

Summary

Introduction

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. 2 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. 5 Neuroscience Research Institute & Department of Neurobiology, Peking University Health Science Center, Beijing 100191, China. 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. One important function of intrinsic plasticity is to shape the input-output information flow from dendrites to axon terminals, through modulating expression levels or biophysical properties of various ion channels localized to different neuronal compartments[4,5,6]. Despite the importance of intrinsic neuroplasticity in physiological and pathological processes in the brain, the underlying molecular mechanisms are still poorly understood

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