Neurotransmitter identity and electrophysiological phenotype are genetically coupled in midbrain dopaminergic neurons

Mónica Tapia,Béatrice Marquèze-Pouey,Jean-Marc Goaillard,Christine Formisano-Tréziny,Kazuto Kobayashi,Pierre Baudot,Martial A Dufour,Jean Gabert,Simone Temporal,Manon Lasserre

doi:10.1038/s41598-018-31765-z

Abstract

Most neuronal types have a well-identified electrical phenotype. It is now admitted that a same phenotype can be produced using multiple biophysical solutions defined by ion channel expression levels. This argues that systems-level approaches are necessary to understand electrical phenotype genesis and stability. Midbrain dopaminergic (DA) neurons, although quite heterogeneous, exhibit a characteristic electrical phenotype. However, the quantitative genetic principles underlying this conserved phenotype remain unknown. Here we investigated the quantitative relationships between ion channels’ gene expression levels in midbrain DA neurons using single-cell microfluidic qPCR. Using multivariate mutual information analysis to decipher high-dimensional statistical dependences, we unravel co-varying gene modules that link neurotransmitter identity and electrical phenotype. We also identify new segregating gene modules underlying the diversity of this neuronal population. We propose that the newly identified genetic coupling between neurotransmitter identity and ion channels may play a homeostatic role in maintaining the electrophysiological phenotype of midbrain DA neurons.

Highlights

Most neuronal types have a well-defined electrophysiological phenotype that they reliably establish and maintain over their lifetime
A complete understanding of the genesis and stability of electrical phenotype can only be achieved using systems-level approaches simultaneously investigating the levels of expression of most of the ion channels expressed by a given neuronal type
We investigated the levels of expression of several voltage-gated ion channels in midbrain DA neurons using single-cell reverse transcription quantitative PCR

Summary

Introduction

Most neuronal types have a well-defined electrophysiological phenotype that they reliably establish and maintain over their (sometimes very long) lifetime. Midbrain DA neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) in vitro display a characteristic low-frequency pacemaking activity, a broad action potential and a hyperpolarization-induced sag These properties exhibit significant cell-to-cell quantitative variations[5,17,18], the combination of these features represents a qualitative fingerprint making midbrain DA neurons immediately distinguishable from their neighboring GABAergic neurons of the substantia nigra pars reticulata (SNr)[19,20]. How DA neurons acquire this specific electrophysiological signature and maintain it is a question that still awaits a complete answer As these neurons are spontaneously active in the absence of synaptic inputs, much emphasis has been put on the study of their voltage-gated conductances, and many ion channel types have www.nature.com/scientificreports/. The newly identified genetic coupling was found in all midbrain DA neurons, suggesting that the rules underlying the definition and stability of their electrophysiological phenotype are conserved

Methods

Results

Conclusion