Pharmacological Antagonism of T-Type Calcium Channels Constrains Rebound Burst Firing in Two Distinct Subpopulations of GABA Neurons in the Rat Ventral Tegmental Area: Implications for α-Lipoic Acid

Abstract

The ventral tegmental area (VTA) is a midbrain region highly involved in motivation and reward. A large body of work has investigated synaptic plasticity and ion channel excitability in this area, which has strong implication in drug abuse. We recently provided electrophysiological and pharmacological evidence that the CaV3.1 isoform of T-type voltage-gated calcium channels contributes to the excitability of VTA dopamine (DA) neurons. However, the role of T-channels in excitability of VTA gamma-amino-butyric acid (GABA) neurons remained unaddressed. Here, with a population study of rat VTA GABA neurons, we provide evidence that T-channels contribute to rebound spiking activity in two phenotypically distinct subpopulations of GABAergic neurons, each with differing electrophysiological characteristics. Additionally, we provide the first study to investigate the effect of α-lipoic acid (ALA) on ion channels in mesolimbic reward circuitry. Taken together, our population study and pharmacology experiments implicate T-channels as a target for therapies aimed at tempering VTA and mesolimbic circuit excitability.

Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

“…It is well documented that I h is present in both dopamine and non-dopamine neurons (Jones and Kauer, 1999; Margolis et al, 2006), including neurons expressing GAD (Chieng et al, 2011; Margolis et al, 2012; Ntamati et al, 2018), VGaT (Woodward et al, 2019) or VGluT2 (Hnasko et al, 2012). We extended these observations by showing that I h is present in less than half of the glutamate-GABA co-releasing neurons, about half of the glutamate-releasing neurons and in more than 90% of the GABA-releasing neurons.…”

“…Given that previous studies have shown hyperpolarization-induced rebound burst firing in a subset of VTA dopamine and non-dopamine neurons mediated by I h (Tateno and Robinson, 2011) or T-type calcium channels (Tracy et al, 2018, Woodward et al, 2019), we next tested the extent to which rebound firing occurs in the three classes of VTA neurons. After holding the resting membrane potential at −100 mV for 1 sec and then releasing that clamp, approximately 25% of VGluT2 + VGaT + neurons showed rebound firing with short bursts of 2-4 APs (12/48 neurons, 10 mice; Figure 5), and this response was stable over repeated trials (Figure 5-suplement figure 1).…”

“…Previous studies found hyperpolarization-induced rebound burst firing in subsets of VTA dopamine and non-dopamine neurons mediated by I h (Tateno and Robinson, 2011) or T-type calcium channels (Tracy et al, 2018, Woodward et al, 2019). We found the same types of responses in subpopulations of glutamate-GABA co-releasing, glutamate-releasing and GABA-releasing neurons.…”

“…We found the same types of responses in subpopulations of glutamate-GABA co-releasing, glutamate-releasing and GABA-releasing neurons. A recent VTA electrophysiological study in a VGaT Knock-in rat line expressing the fluorescent protein Venus reported two populations with different rebound firing properties (type 1 with low threshold calcium spikes during rebound firing, and type two with post hyperpolarizing action potentials during rebound firing) of VGaT-Venus neurons expressing T-channels (Woodward et al, 2019). Given that we detected T-channel mediated rebound in glutamate-GABA co-releasing and GABA-releasing neurons, and both classes of neurons express VGaT (Root et al, 2018b), it remains to be determined the extent to which these two classes of neurons overlapped with those detected in rat VTA VGaT-Venus neurons.…”

Ventral tegmental area GABA, glutamate, and glutamate‐GABA neurons are heterogeneous in their electrophysiological and pharmacological properties

“…Given that previous studies have shown hyperpolarization-induced rebound burst firing in a subset of VTA dopamine and non-dopamine neurons mediated by I h (Tateno and Robinson, 2011) or T-type calcium channels (Tracy et al, 2018, Woodward et al, 2019, we next tested the extent to which rebound firing occurs in the three classes of VTA neurons. After holding the resting membrane potential at -100 mV for 1 sec and then releasing that clamp, approximately 25% of was not certified by peer review) is the author/funder.…”