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

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.

Functional Neuroanatomy of the Rat Nucleus Incertus–Medial Septum Tract: Implications for the Cell-Specific Control of the Septohippocampal Pathway

“…Further studies are needed to unequivocally determine whether MS innervated NI cells that burst under in vivo conditions, belong to the type II neurons described in the current study, but cited in vivo and ex vivo characteristics [bursting phenotype and the expression of burst-firing patterns underlying, putative T-type calcium currents (Arshaad et al, 2021), respectively], support this conclusion. It can therefore be assumed that distinctive intrinsic properties and synaptic inputs to type I NI neurons innervating the MS, interact to select and propagate information that influences MS-dependent theta rhythm and related behaviors (Nuñez et al, 2006;Ma et al, 2009Ma et al, , 2013Lu et al, 2020;Gil-Miravet et al, 2021).…”

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies

“…The anxious environment-induced type 2 theta oscillation and associated anxiety were shown to be dependent on the MS cholinergic neurons because lesion or inactivation of MS cholinergic neurons reduced them ( Nag et al, 2009 ). They are also regulated by phospholipase C β4 in the MS and a T-type voltage-gated calcium channel (Cav 3.2), which is highly expressed in the septo-hippocampal axis ( Shin et al, 2009 ; Gangarossa et al, 2014 ; Arshaad et al, 2021 ). The anxiety-related theta oscillations in the septo-hippocampal axis are externally regulated.…”

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance

“…Therefore, alterations in theta activity observed in Ca v 3.2 −/− mice are likely to be based on the atropine-sensitive subtype II theta entity. These results were further confirmed by urethane injection studies, which revealed a significant increase in type II theta activity in Ca v 3.2-deficient mice compared to controls [ 138 ]. Pharmacodynamically, urethane exhibits a multitarget character, exerting both stimulatory and inhibitory action on various voltage- and ligand-gated ion channels.…”

“…Recently, we investigated the role of Ca v 3.2 T-type Ca 2+ channels in initiation, maintenance, and modulation of hippocampal theta oscillations and the immanent molecular/biochemical and in vivo electrophysiological mechanisms. We showed that Ca v 3.2 −/− mice display enhanced type II theta activity in spontaneous 24 h long-term EEG recordings [ 138 ]. Importantly, the increase in theta/alpha relative EEG power was most prominent during the inactive state of the light cycle, as well as the dark cycle.…”

“…It is important to stress that both Ca v 3.2 +/+ and Ca v 3.2 −/− mice displayed typical circadian activity profiles. No significant differences in motor activity were detected between both genotypes, indicating that alterations in the hippocampal theta/alpha band were not based on changes in locomotion [ 138 ].…”