Enhanced hippocampal type II theta activity AND altered theta architecture in mice lacking the Cav3.2 T-type voltage-gated calcium channel

Muhammad Imran Arshaad,Karl Broich,Christina Henseler,Jürgen Hescheler,Magdalena Elisabeth Siwek,Dan Ehninger,Marco Weiergräber,Agapios Sachinidis,Anna Papazoglou,Johanna Daubner

doi:10.1038/s41598-020-79763-4

Abstract

T-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2−/− mice revealed robust increase in relative power in the theta (4–8 Hz) and theta-alpha (4–12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2−/− mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2−/− mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.

Highlights

Abbreviations active state (AS) Active state CA Cornu ammonis Calibrated Normalized Relative Quantity (CNRQ) Calibrated normalized relative quantity DAG Diacylglycerole DC Dark cycle DHP Dihydropyridine EC Entorhinal cortex GABA Gamma-aminobutyric acid G-protein coupled receptors (GPCR) G-protein coupled receptor GT Genotype HVA High voltage-activated i.p
The so-called septal pacemakerhippocampal follower model is widely accepted, based on studies by Hangya et al who showed that a subgroup of GABAergic medial septum (MS) neurons operates as the pacemaker structure by forwarding rhythmic activity on hippocampal pyramidal cells and interneurons[11]
Previous studies have shown that C av3.2 Ca2+ channels are crucial for hippocampal long-term potentiation (LTP), cued-context fear conditioning tasks and passive avoidance strategies[45]

Summary

Introduction

Abbreviations AS Active state CA Cornu ammonis CNRQ Calibrated normalized relative quantity DAG Diacylglycerole DC Dark cycle DHP Dihydropyridine EC Entorhinal cortex GABA Gamma-aminobutyric acid GPCR G-protein coupled receptor GT Genotype HVA High voltage-activated i.p. Inactivation of hippocampal PLCβ1 or septal PLCβ4 resulted in total loss or major mitigation of synchronized theta oscillations[19,20] Based on their cellular and subcellular expression pattern and functional contribution to dendritic resonance phenomena, voltage-gated Ca2+ channels (VGCCs) represent key components in theta genesis though the exact mechanisms remain to be determined[21,22]. Only type II hippocampal theta was enhanced in the MS knockdown animals, whereas both type I and type II theta rhythms were increased in global Cav3.1−/− mice This specific effect is potentially related to a strong increase in excitability of septohippocampal GABAergic neurons and a shift from the burst to the tonic firing p attern[43]. Ca2+ channels in initiation, maintenance, and modulation of hippocampal theta oscillations and the underlying molecular and electrophysiological mechanisms

Methods

Results

Conclusion