Atropine-sensitive hippocampal θ oscillations are mediated by Cav2.3 R-type Ca²⁺ channels

Hippocampal theta oscillations are key elements in numerous behavioral and cognitive processes. Based on the dualistic theory of theta oscillations, one can differentiate between atropine-sensitive and atropine-insensitive theta subtypes. Urethane-induced atropine-sensitive theta oscillations are driven by muscarinic signal transduction pathways through G protein q/11 alpha subunit (Gα(q/11)), phospholipase β( ¼) (PLCβ( ¼), inositol trisphosphate (InsP₃), diacylglycerole (DAG), and protein kinase C (PKC). Recent findings illustrate that Ca(v)2.3 Ca²⁺ channels are important targets of muscarinic signaling in the hippocampus mediating plateau potential generation, epileptiform burst activity, and complex rhythm generation in the septohippocampal network. To investigate the physiological implications of Ca(v)2.3 Ca²⁺ channels in hippocampal theta oscillations we performed radiotelemetric intrahippocampal (cornu ammonis (CA1)) recordings in urethane (800 mg/kg, i.p.) and atropine (50 mg/kg, i.p.) treated Ca(v)2.3⁺/⁺ and Ca(v)2.3⁻/⁻ mice followed by wavelet analysis of EEG data. Our results demonstrate that Ca(v)2.3 ablation, unlike PLCβ₁ deletion, does not result in complete abolishment of urethane-induced theta oscillations and that both mean and total theta duration is not significantly inhibited by subsequent atropine treatment, indicating that Ca(v)2.3 Ca²⁺ channels are important mediators of atropine-sensitive theta. Although theta frequency remained unchanged between both genotypes, the temporal characteristics of theta distribution, that is, theta architecture were significantly affected by the loss of Ca(v)2.3 Ca²⁺ channels. Our data suggest, for the first time, that Ca(v)2.3 voltage-gated Ca²⁺ channels (VGCC) are an important factor in septohippocampal synchronization associated with theta oscillation.