CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons

Tracy, Matthew; Tešić, Vesna; Stamenić, Tamara Timić; Joksimović, Srđan; Busquet, Nicolas; Jevtović-Todorović, Vesna; Todorović, Slobodan M.

doi:10.1016/j.neuropharm.2018.03.028

Cited by 12 publications

(16 citation statements)

References 43 publications

(59 reference statements)

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“…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).…”

Section: Resultsmentioning

confidence: 99%

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

Miranda‐Barrientos

Chambers

Mongia

et al. 2020

Preprint

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The ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT− and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2− VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.Impact StatementSome physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.

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Section: Resultsmentioning

confidence: 99%

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

Miranda‐Barrientos

Chambers

Mongia

et al. 2020

Preprint

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“…Our recent patch-clamp recordings in acute VTA brain slices from WT rats clearly demonstrated expression of classic T-type currents that underlie post-inhibitory rebound burst firing in a subset of VTA neurons (Tracy et al, 2018). However, it is well known that the VTA contains heterogeneous populations of dopaminergic neurons, as well as both inhibitory and excitatory interneurons, all of which play critical roles in regulating motivated behaviors (Morales and Margolis, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we confirm that VTA GABAergic neurons heterogeneously display a voltage sag characteristic of an Ih current at hyperpolarizing potentials, though it is worth noting that among our sample population, Type 2 neurons almost ubiquitously showed a voltage sag upon hyperpolarization. It is also worth noting that for practical reasons all recordings in this and our previuos study (Tracy et al, 2018) were done at room temperature. However, previous studies reported strong temperature dependence of both Ih and T-channel activation (Vargas and Lucero, 1999; Iftinca et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…As they recover from inactivation at around -80 mV, a small hyperpolarizing current can drive a calcium influx that allows for rapid burst firing from lower membrane potentials in neurons containing T-channels. Recently, our lab investigated the role of the Ca V 3.1 isoform of T-channels in VTA neuronal excitability and confirmed the presence of T-channels on both DA and non-DA neurons using a tyrosine-hydroxylase (TH) Tg-GFP rat and mouse genetics with Ca V 3.1 knockout mice (Tracy et al, 2018). Interestingly, we found that while some DA neurons expressed T-channels, it was actually likely that T-channel dependent rebound bursting was somewhat more prominently expressed in non-DA neurons.…”

Section: Introductionmentioning

confidence: 96%

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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

Woodward

Tešić²,

Stamenić³

et al. 2019

Front. Pharmacol.

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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.

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“…Cav3.1 subunits were reported to be important in weight maintenance and sleep/wake activity, which indicated that Cav3.1 could be a potential antiobesity target [134]. In another report, knockdown of Cav3.1 or its inhibition significantly decreased neuronal excitability in the ventral tegmental area, as a result of decreased T-type currents and rebound burst firing in mouse or rat neurons [135]. Alpha(1G)-deficient mice are resistant to absence seizure due to the lack of burst firing in thalamocortical relay neurons [136], while Cav3.1 overexpression was reported to induce absence seizure [137].…”

Section: Cav31mentioning

confidence: 98%

Pathophysiological roles and therapeutic potential of voltage-gated ion channels (VGICs) in pain associated with herpesvirus infection

Zhang

Martin‐Caraballo

2020

Cell Biosci

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Herpesvirus is ranked as one of the grand old members of all pathogens. Of all the viruses in the superfamily, Herpes simplex virus type 1 (HSV-1) is considered as a model virus for a variety of reasons. In a permissive non-neuronal cell culture, HSV-1 concludes the entire life cycle in approximately 18-20 h, encoding approximately 90 unique transcriptional units. In latency, the robust viral gene expression is suppressed in neurons by a group of noncoding RNA. Historically the lesions caused by the virus can date back to centuries ago. As a neurotropic pathogen, HSV-1 is associated with painful oral lesions, severe keratitis and lethal encephalitis. Transmission of pain signals is dependent on the generation and propagation of action potential in sensory neurons. T-type Ca 2+ channels serve as a preamplifier of action potential generation. Voltage-gated Na + channels are the main components for action potential production. This review summarizes not only the voltage-gated ion channels in neuropathic disorders but also provides the new insights into HSV-1 induced pain.

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CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons

Cited by 12 publications

References 43 publications

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

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

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

Pathophysiological roles and therapeutic potential of voltage-gated ion channels (VGICs) in pain associated with herpesvirus infection

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