Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders

Juanjiangmeng Du; Sean Simmons; Andreas Brunklaus; Xian Adiconis; Cynthia C Hession; Zhanyan Fu; Yinqing Li; Reut Shema; Rikke S Møller; Boaz Barak; Guoping Feng; Miriam Meisler; Stephan Sanders; Holger Lerche; Arthur J Campbell; Steven McCarroll; Joshua Z Levin; Dennis Lal

doi:10.1016/j.ejpn.2019.12.019

Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders

Eur J Paediatr Neurol. 2020 Jan:24:129-133. doi: 10.1016/j.ejpn.2019.12.019. Epub 2019 Dec 28.

Authors

Juanjiangmeng Du¹, Sean Simmons², Andreas Brunklaus³, Xian Adiconis⁴, Cynthia C Hession⁴, Zhanyan Fu⁴, Yinqing Li⁴, Reut Shema⁴, Rikke S Møller⁵, Boaz Barak⁶, Guoping Feng⁷, Miriam Meisler⁸, Stephan Sanders⁹, Holger Lerche¹⁰, Arthur J Campbell⁴, Steven McCarroll¹¹, Joshua Z Levin⁴, Dennis Lal¹²

Affiliations

¹ Cologne Center for Genomics, University of Cologne, University Hospital Cologne, Cologne, Germany.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Cambridge, MA, USA.
³ The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK; School of Medicine, University of Glasgow, Glasgow, UK. Electronic address: andreas.brunklaus@nhs.net.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
⁶ McGovern Institute for Brain Research and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; McGovern Institute for Brain Research and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA.
⁸ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
¹⁰ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹² Cologne Center for Genomics, University of Cologne, University Hospital Cologne, Cologne, Germany; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Cambridge, MA, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA. Electronic address: lald@ccf.org.

PMID: 31928904
DOI: 10.1016/j.ejpn.2019.12.019

Abstract

The four voltage-gated sodium channels SCN1/2/3/8A have been associated with heterogeneous types of developmental disorders, each presenting with disease specific temporal and cell type specific gene expression. Using single-cell RNA sequencing transcriptomic data from humans and mice, we observe that SCN1A is predominantly expressed in inhibitory neurons. In contrast, SCN2/3/8A are profoundly expressed in excitatory neurons with SCN2/3A starting prenatally, followed by SCN1/8A neonatally. In contrast to previous observations from low resolution RNA screens, we observe that all four genes are expressed in both excitatory and inhibitory neurons, however, exhibit differential expression strength. These findings provide molecular evidence, at single-cell resolution, to support the hypothesis that the excitatory/inhibitory (E/I) neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain homeostasis and neurological diseases. Modulating the E/I expression balance within cell types of sodium channels could serve as a potential strategy to develop targeted treatment for Na_V-associated neuronal developmental disorders.

Keywords: Neurodevelopmental disorders; SCN1A; SCN2A; SCN3A; SCN8A; Sodium channel; Transcriptome.

MeSH terms

Animals
Brain / metabolism*
Developmental Disabilities / genetics
Developmental Disabilities / metabolism*
Humans
Mice
Neurons / metabolism*
Voltage-Gated Sodium Channels / genetics
Voltage-Gated Sodium Channels / metabolism*

Substances

Voltage-Gated Sodium Channels