Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits.

Viktor János Oláh,David Lukacsovich,János Szabadics,Csaba Földy,Andrea Lőrincz,Antónia Arszovszki,Jochen Winterer,Zoltan Nusser

doi:10.7554/elife.58515

Viktor János Oláh, David Lukacsovich + Show 6 more

Open Access

https://doi.org/10.7554/elife.58515

Copy DOI

Abstract

CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells' whole transcriptome, can determine cell-type identity.

Highlights

The biophysical and morphological properties of complementary GABAergic cell classes are tuned for regulating the activity of the much more populous principal cells in broad temporal and spatial domains
A large portion of CCKexpressing hippocampal interneurons (CCK+IN) show state-dependent firing in the CA3 area
Our results describe two novel CCK+IN populations, TOR and RS cells in the CA3, and provide a mechanistic explanation for their activity patterns during 8–15 Hz theta oscillations

Summary

Introduction

The biophysical and morphological properties of complementary GABAergic cell classes are tuned for regulating the activity of the much more populous principal cells in broad temporal (from second to sub-millisecond; Hu et al, 2014; Overstreet-Wadiche and McBain, 2015) and spatial (from axons to distal dendrites Freund and Buzsaki, 1996) domains. Emerging evidence using single-cell transcriptomics suggests that the number of GABAergic types may be higher than previously recognized (Foldy et al, 2016; Fuzik et al, 2016; Harris et al, 2018; Que et al, 2019; Tasic, 2018; Zeisel et al, 2015). While these studies accelerated cell classification efforts by identifying a large number of genes that appear to define further subtypes in neuronal taxonomy, the functional relevance of most transcriptomic marker genes remain poorly understood. To better understand the relationship between gene expression and physiological function, and how these properties define neuronal types, we employed a multidisciplinary approach to study a previously unrecognized level of functional diversity among CCKexpressing hippocampal interneurons (CCK+IN) in rat CA3 area

Objectives

Methods

Results

Conclusion