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

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 develop...

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Published in:eLife 2024-12, Vol.12
Main Authors: Wang, Jing, Su, Min, Zhang, Dongmei, Zhang, Ludi, Niu, Chenxu, Li, Chaoyi, You, Shuangzhu, Sang, Yuqi, Zhang, Yongxue, Du, Xiaona, Zhang, Hailin
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Behavior, Animal
cation channels
Depression - metabolism
Depression - physiopathology
Depression, Mental
dopaminergic neurons
Dopaminergic Neurons - metabolism
Dopaminergic Neurons - physiology
Male
Mice
Mice, Inbred C57BL
NALCN
Neurons
Stress, Psychological - metabolism
TRPC6 Cation Channel - genetics
TRPC6 Cation Channel - metabolism
TRPC6 channel
ventral tegmental area
Ventral Tegmental Area - metabolism
Ventral Tegmental Area - physiopathology
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.88319