Altered Expression of NALCN and TRPC6 Channels Contributes to Reduced Firing Activity of VTA Dopaminergic Neurons in a Mouse Model of Depression

Conceptos Básicos

Down-regulation of NALCN and TRPC6 channels in VTA dopaminergic neurons leads to reduced neuronal firing and depression-like behavior in a mouse model of chronic stress.

Resumen

This study investigates the mechanisms underlying the altered firing activity of ventral tegmental area (VTA) dopaminergic (DA) neurons in a mouse model of depression. The authors first profiled the expression of non-selective cation channels (NSCCs) in VTA DA neurons using single-cell RNA sequencing. They found that NALCN and TRPC6 channels are prominently expressed in these neurons and play crucial roles in regulating their subthreshold depolarization and spontaneous firing.

Specifically, the authors demonstrate that:

1. Extracellular Na+ influx, but not Ca2+, contributes to the subthreshold depolarization that drives the spontaneous firing of VTA DA neurons.

2. NALCN channels mediate a significant portion of this Na+ influx and are essential for maintaining the resting membrane potential and spontaneous firing of VTA DA neurons. Knockdown of NALCN in VTA DA neurons almost completely silences their firing.

3. TRPC6 channels also contribute to the subthreshold depolarization and spontaneous firing of VTA DA neurons. Selective knockdown of TRPC6 substantially reduces their firing activity.

Furthermore, the authors show that in a mouse model of chronic mild unpredictable stress (CMUS), which exhibits depression-like behaviors, the firing activity of VTA DA neurons is significantly reduced compared to control mice. This reduction in firing is accompanied by a down-regulation of TRPC6 protein expression in the VTA.

Collectively, these findings suggest that the decreased expression/function of NALCN and TRPC6 channels in VTA DA neurons is a key mechanism underlying the reduced neuronal firing and the development of depression-like behaviors in the CMUS mouse model. This provides important insights into the pathophysiology of mood disorders.

Estadísticas

The resting membrane potential of VTA DA neurons was hyperpolarized from -48.11 ± 0.99 mV to -59.93 ± 1.51 mV when extracellular Na+ was replaced with NMDG.
Knockdown of NALCN in VTA DA neurons reduced their spontaneous firing frequency from 1.60 ± 0.15 Hz to 0.08 ± 0.02 Hz.
Knockdown of TRPC6 in VTA DA neurons reduced their spontaneous firing frequency from 1.88 ± 0.16 Hz to 0.43 ± 0.07 Hz.
VTA DA neurons from CMUS mice exhibited a significantly lower spontaneous firing frequency (0.89 ± 0.07 Hz) compared to control mice (1.63 ± 0.11 Hz).
TRPC6 protein expression in the VTA was decreased by 50% in CMUS mice compared to control mice.

Citas

"Down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice."
"Knockdown of NALCN in the VTA DA neurons almost completely silenced the firing of the male and female VTA DA neurons."
"Knockdown of TRPC6 resulted in a substantial reduction in the spontaneous firing frequency... of the VTA DA neurons."

Ideas clave extraídas de

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

by Wang,J., Su,... a las www.biorxiv.org 04-15-2023

https://www.biorxiv.org/content/10.1101/2023.04.14.536970v3

Consultas más profundas

How do the altered expression and function of NALCN and TRPC6 channels in VTA DA neurons impact the activity of their downstream target brain regions, such as the nucleus accumbens and prefrontal cortex, and contribute to the development of depression-related behaviors

The altered expression and function of NALCN and TRPC6 channels in VTA DA neurons can have significant implications for the activity of their downstream target brain regions, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC), and contribute to the development of depression-related behaviors. NALCN and TRPC6 channels play crucial roles in mediating the subthreshold depolarizing currents and driving the firing of action potentials in VTA DA neurons. When these channels are down-regulated, as seen in conditions like chronic mild unpredictable stress (CMUS) depressive mice, it leads to reduced activity of projection-specific VTA DA neurons. This reduced activity can result in altered neurotransmitter release in the NAc, PFC, and other target regions, impacting the overall function of the mesocorticolimbic dopaminergic system. The dysregulation of dopamine signaling in these regions is closely linked to mood and emotion-related behaviors, including depression. Therefore, the decreased firing of VTA DA neurons due to the down-regulation of NALCN and TRPC6 channels can disrupt the balance of neurotransmission in the NAc and PFC, contributing to the manifestation of depression-like behaviors.

What other ion channels or signaling pathways might interact with NALCN and TRPC6 to modulate the excitability of VTA DA neurons in physiological and pathological conditions

In addition to NALCN and TRPC6 channels, several other ion channels and signaling pathways may interact to modulate the excitability of VTA DA neurons in both physiological and pathological conditions. One such ion channel is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, which has been implicated in regulating the spontaneous firing of midbrain DA neurons. While HCN channels were found not to be involved in the spontaneous firing of VTA DA neurons in adult mice, they may still play a role in modulating excitability under certain conditions or in specific neuronal subpopulations. Additionally, voltage-gated Na+ channels, high-threshold-activated Ca2+ channels, and potassium channels (e.g., Kv2, large conductance calcium-activated potassium channels) are known to contribute to the regulation of firing activity in midbrain DA neurons. Signaling pathways involving neurotransmitters like glutamate and GABA, as well as neuromodulators such as dopamine itself, can also interact with ion channels to fine-tune the excitability of VTA DA neurons. Furthermore, intracellular signaling cascades, including cAMP-PKA pathways and calcium signaling, can influence the activity of ion channels and impact the firing patterns of VTA DA neurons.

Could pharmacological targeting of NALCN and TRPC6 channels represent a novel therapeutic strategy for the treatment of depression and other mood disorders

Pharmacological targeting of NALCN and TRPC6 channels presents a promising avenue for the development of novel therapeutic strategies for the treatment of depression and other mood disorders. Given the critical role of these channels in regulating the firing activity of VTA DA neurons, modulating their function could potentially restore the balance of neurotransmission in the mesocorticolimbic dopaminergic system. By enhancing the activity of NALCN and TRPC6 channels, it may be possible to increase the firing of VTA DA neurons and promote the release of dopamine in target regions like the NAc and PFC, thereby alleviating depressive symptoms. Conversely, inhibiting these channels could be explored as a way to reduce hyperexcitability and restore normal firing patterns in conditions where VTA DA neuron activity is dysregulated. Developing specific agonists or antagonists targeting NALCN and TRPC6 channels could offer more precise and effective treatments for mood disorders, potentially with fewer side effects compared to traditional pharmacological interventions. Further research into the mechanisms of action and potential therapeutic benefits of targeting NALCN and TRPC6 channels is warranted to explore their full therapeutic potential in the management of depression.