T-Type Calcium Channels Contribute to Burst Firing in a Subpopulation of Medial Habenula Neurons

Abstract

Action potential (AP) burst firing caused by the activation of low-voltage-activated T-type Ca²⁺ channels is a unique mode of neuronal firing. T-type channels have been implicated in diverse physiological and pathophysiological processes, including epilepsy, autism, and mood regulation, but the brain structures involved remain incompletely understood. The medial habenula (MHb) is an epithalamic structure implicated in anxiety-like and withdrawal behavior. Previous studies have shown that MHb neurons fire tonic APs at a frequency of ∼2–10 Hz or display depolarized low-amplitude membrane oscillations. Here, we report in C57BL/6J mice that a subpopulation of MHb neurons are capable of firing transient, high-frequency AP bursts mediated by T-type channels. Burst firing was observed following rebounding from hyperpolarizing current injections or during depolarization from hyperpolarized membrane potentials in ∼20% of MHb neurons. It was rarely observed at baseline but could be evoked in MHb neurons displaying different initial activity states. Further, we show that T-type channel mRNA, in particular Ca_v3.1, is expressed in the MHb in both cholinergic and substance P-ergic neurons. Pharmacological Ca_v3 antagonism blocked both burst firing and evoked Ca²⁺ currents in MHb neurons. Additionally, we observed high-frequency AP doublet firing at sustained depolarized membrane potentials that was independent of T-type channels. Thus, there is a greater diversity of AP firing patterns in MHb neurons than previously identified, including T-type channel-mediated burst firing, which may uniquely contribute to behaviors with relevance to neuropsychiatric disease.