The cation channel mechanisms of subthreshold inward depolarizing currents in the mice VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; Department of Chinese Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China
Min Su
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; Yiling Pharmaceutical Company, Shijiazhuang, China
Dongmei Zhang
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; Department of Clinical Pharmacy, Xingtai Ninth Hospital, Xingtai, China
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
Chenxu Niu
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
Chaoyi Li
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
Shuangzhu You
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
Yuqi Sang
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; College of Chemical Engineering, Shijiazhuang University, Shijiazhuang, China; Shijiazhuang Key Laboratory of Targeted Drugs Research and Efficacy Evaluation, Shijiazhuang, China
Yongxue Zhang
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; Department of Pharmacy, Handan First Hospital, Handan, China
Xiaona Du
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China
Department of Pharmacology, Hebei Medical University, Shijiazhuang, China; Department of Psychiatry, The First Hospital of Hebei Medical University, Mental Health Institute of Hebei Medical University, Shijiazhuang, China
The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.
