Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, United States.
Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, United States.
Neuropharmacology. 2018 Jun;135:343-354. doi: 10.1016/j.neuropharm.2018.03.028. Epub 2018 Mar 23.
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, Ca3.1 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 Ca3.1 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 Ca3.1 KO mice, suggesting a tangible role for 3.1 T-type channels in drug response. We conclude that pharmacological targeting of Ca3.1 isoform of T-channels may be a novel approach for the treatment of disorders of mesolimbic reward system.
最近的数据表明，电压门控钙通道在调节中脑边缘奖励系统神经元的兴奋性方面起作用。虽然大多数研究的注意力都集中在高电压 L 型钙通道活性上，但低电压门控 T 型钙通道（T 型通道）的存在和作用尚未得到很好的探索。因此，我们利用野生型（WT）大鼠和小鼠、Ca3.1 敲除（KO）小鼠和 TH-eGFP 敲入（KI）大鼠在青春期动物的急性水平脑切片中研究了腹侧被盖区（VTA）神经元中的 T 型通道特性。在电压钳实验中，我们首先评估了 WT 大鼠中的 T 型通道活性，其具有电压依赖性激活和失活的特征，以及宏观电流动力学的特征交叉模式。WT 小鼠和 WT 大鼠的 T 电流动力学相似，但 Ca3.1 KO 小鼠中的 T 电流被消除。在随后的电流钳实验中，我们观察到 WT 大鼠中的一部分神经元存在超极化诱导的爆发性放电，以及 TH-eGFP KI 大鼠中的多巴胺能和非多巴胺能神经元。在应用泛选择性 T 型通道阻滞剂 TTA-P2 后，所有测试细胞的爆发性放电都显著抑制。在行为评估中，WT 小鼠中 MK-801（地佐辛）注射引起的急性运动增加在 Ca3.1 KO 小鼠中被消除，这表明 3.1 T 型通道在药物反应中具有明显的作用。我们得出结论，药理学靶向 Ca3.1 型 T 型通道可能是治疗中脑边缘奖励系统障碍的一种新方法。
