The Role of Transient Receptor Potential Canonical Type 6 (TRPC6) Channels in Regulating Ventral Tegmental Area Dopamine Neuron Physiology and Function

Abstract

Ventral tegmental area (VTA) dopamine (DA) neurons integrate neurotransmitter and neuropeptide signals to encode reward-related information. Extensive work from our laboratory and others has shown how specific subpopulations of VTA-DA neurons, defined by the expression of neuropeptide G-protein coupled receptors (GPCRs), regulate motivated behavior. These neuropeptide GPCRs activate signaling pathways that lead to increases in intracellular calcium ions, affecting cellular function and ultimately behavior. However, the mechanisms of these increases in intracellular calcium ions remain largely unexplored. Transient receptor potential canonical (TRPC) channels are a class of calcium-permeable ion channels, and our laboratory has identified TRPC type 6 (TRPC6) channels as the most abundantly expressed TRPC channel in VTA-DA neurons. Given strong evidence linking TRPC channel activation with neuropeptide receptor signaling, neuropeptidergic modulation of calcium signaling dynamics in VTA-DA neurons, and the widely established role of DA neurons encoding reward-related information, we hypothesized that TRPC6 channels are critical regulators of neuropeptidergic signaling pathways in VTA-DA neurons. To explore this, we disrupted TRPC6 channel function in DA neurons of the adult mouse VTA and performed ex vivo calcium imaging, whole-cell patch-clamp electrophysiology and in vivo fiber photometry during consummatory tasks. We demonstrate a novel mechanism by which TRPC6 channels regulate distinct aspects of neuropeptide receptor-activated calcium signals in VTA-DA neurons but make little contribution to the calcium dynamics associated with metabotropic neurotransmitter receptor signaling. Additionally, we show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in a homeostatic state-dependent manner. Future studies will explore the single-cell calcium dynamics of TRPC6 channel-mediated signaling in vivo, the signaling complexes involved in the control of TRPC6 channel activation by neuropeptide receptors, and the role of other neuropeptidergic inputs to VTA-DA neurons that influence TRPC6 channel recruitment under varying homeostatic states.