RRC ID 50369
Author Tracy ME, Tesic V, Stamenic TT, Joksimovic SM, Busquet N, Jevtovic-Todorovic V, Todorovic SM.
Title CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons.
Journal Neuropharmacology
Abstract Recent data have implicated voltage-gated calcium channels in the regulation of the excitability of neurons within the mesolimbic reward system. While the attention of most research has centered on high voltage L-type calcium channel activity, the presence and role of the low voltage-gated T-type calcium channel (T-channels) has not been well explored. Hence, we investigated T-channel properties in the neurons of the ventral tegmental area (VTA) utilizing wild-type (WT) rats and mice, CaV3.1 knock-out (KO) mice, and TH-eGFP knock-in (KI) rats in acute horizontal brain slices of adolescent animals. In voltage-clamp experiments, we first assessed T-channel activity in WT rats with characteristic properties of voltage-dependent activation and inactivation, as well as characteristic crisscrossing patterns of macroscopic current kinetics. T-current kinetics were similar in WT mice and WT rats but T-currents were abolished in CaV3.1 KO mice. In ensuing current-clamp experiments, we observed the presence of hyperpolarization-induced rebound burst firing in a subset of neurons in WT rats, as well as dopaminergic and non-dopaminergic neurons in TH-eGFP KI rats. Following the application of a pan-selective T-channel blocker TTA-P2, rebound bursting was significantly inhibited in all tested cells. In a behavioral assessment, the acute locomotor increase induced by a MK-801 (Dizocilpine) injection in WT mice was abolished in CaV3.1 KO mice, suggesting a tangible role for 3.1 T-type channels in drug response. We conclude that pharmacological targeting of CaV3.1 isoform of T-channels may be a novel approach for the treatment of disorders of mesolimbic reward system.
Volume 135
Pages 343-354
Published 2018-6-1
DOI 10.1016/j.neuropharm.2018.03.028
PII S0028-3908(18)30139-4
PMID 29578032
PMC PMC5975125
MeSH Action Potentials / drug effects Action Potentials / physiology* Animals Calcium Channel Blockers / pharmacology Calcium Channels, T-Type / genetics Calcium Channels, T-Type / metabolism* Dizocilpine Maleate / pharmacology Dopamine / metabolism Excitatory Amino Acid Antagonists / pharmacology Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Mice, Inbred C57BL Mice, Knockout Motor Activity / drug effects Motor Activity / physiology Neurons / drug effects Neurons / metabolism* Rats, Sprague-Dawley Rats, Transgenic Tissue Culture Techniques Ventral Tegmental Area / drug effects Ventral Tegmental Area / metabolism*
IF 4.431
Times Cited 1
Mice RBRC01465