CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons

• Published in: Neuropharmacology Vol. 135; pp. 343 - 354
• Main Authors: Tracy, Matthew E., Tesic, Vesna, Stamenic, Tamara Timic, Joksimovic, Srdjan M., Busquet, Nicolas, Jevtovic-Todorovic, Vesna, Todorovic, Slobodan M.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.06.2018
• Subjects: Burst firing; Dopamine; Low-voltage-activated; Rebound spiking; T-type calcium channel; TTA-P2; Ventral tegmental area; GTP; VTA; DMSO; LTS; Burst firing; ADP; MK-801; TEA-OH; TTX; Rebound spiking; Ventral tegmental area; WT; KI; PBS; eGFP; Dopamine; KO; DAB; T-type calcium channel; TMA-OH; EGTA; AP; Low-voltage-activated; TH; RMP; LVA; Rin; VGCC; TTA-P2; ATP; HF
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.03.028

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. •Subpopulation of neurons of the ventral tegmental area (VTA) express prominent T-type calcium currents.•T-channels support rebound burst firing in a subset of both dopaminergic and non-dopaminergic VTA neurons.•Pan-selective T-channel blocker TTA-P2 completely inhibited rebound bursting in VTA neurons.•MK-801 hyperlocomotion was observed in WT but not in CaV 3.1 KO mice, demonstrating a crucial role of this isoform.•Pharmacological targeting of CaV3.1 isoform of T-channels may be a novel therapeutic approach for the disorders of the mesolimbic reward system.