The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the depression-like behavior

Wang, J.; Su, M.; Zhang, D.; Zhang, L.; Niu, C.; Li, C.; You, S.; Sang, Y.; Zhang, Y.; Du, X.; Zhang, H.

doi:10.1101/2023.04.14.536970

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bioRxiv · 10.1101/2023.04.14.536970

The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the depression-like behavior

Wang, J.·Su, M.·Zhang, D.·Zhang, L.·Niu, C.·Li, C.·You, S.·Sang, Y.·Zhang, Y.·Du, X.·Zhang, H.

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Abstract

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 for 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 condition. 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 neuron 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.

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Wang, J., Su, M., Zhang, D., Zhang, L., Niu, C., Li, C., You, S., Sang, Y., Zhang, Y., Du, X., Zhang, H.. 2023-04-15. The cation channel mechanisms of subthreshold inward depolarizing currents in the VTA dopaminergic neurons and their roles in the depression-like behavior. https://doi.org/10.1101/2023.04.14.536970

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