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

作者：Jing Wang, Min Su, Dongmei Zhang, Ludi Zhang, Chenxu Niu, Chaoyi Li, Shuangzhu You, Yuqi Sang, Yongxue Zhang, Xiaona Du, Hailin Zhang · 发表于：eLife · 年份：2024 · DOI：10.7554/elife.88319.4 · 被引用次数：4 · 研究领域：Ion Channels and Receptors、Circadian rhythm and melatonin、Neuroscience and Neuropharmacology Research

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.