Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels

Abstract

Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1). Several mouse mutants exist that harbor mutations in the orthologous Cacna1a gene. The spontaneous Cacna1a mutants Rolling Nagoya (tgrol), Tottering (tg) and Leaner (tgln) mice exhibit behavioral motor phenotypes, including ataxia. Transgenic knock-in (KI) mouse strains with the human FHM1 R192Q and S218L missense mutations have been generated. R192Q KI mice are non-ataxic, whereas S218L KI mice display a complex behavioral phenotype that includes cerebellar ataxia. Given the dependence of γ-aminobutyric acid type A (GABAA) receptor subunit functioning on localized calcium currents, and the functional link between GABAergic inhibition and ataxia, we hypothesized that cerebellar GABAA receptor expression is differentially affected in Cacna1a mutants and contributes to the ataxic phenotype. Herein we quantified functional GABAA receptors and pharmacologically dissociated cerebellar GABAA receptors in several Cacna1a mutants. We did not identify differences in expression of GABAA receptor subunits or in the number of functional GABAA receptors in the non-ataxic R192Q KI strain. In contrast, tgrol mice had a ~15% decrease in the number of functional GABAA receptors, whereas S218L KI mice showed a ~29% increase. Our data suggest that differential changes in cerebellar GABAA receptor expression profile may contribute to the neurological phenotype of cerebellar ataxia and that targeting GABAA receptors might represent a feasible complementary strategy to treat cerebellar ataxia.

Using the shared genetics of dystonia and ataxia to unravel their pathogenesis

“…Loss of inhibition is thought to be a crucial causal component in the pathogenesis of dystonia (Quartarone and Hallett, 2013), and alterations in GABA A receptors may affect inhibition of action potential firing, thus contributing to disease (Hirose, 2014). Differential expression of GABA A receptors was observed in a SCA6 mouse model caused by mutations in Cacna1a (Kaja et al, 2015). In contrast, mice with PCspecific knockdown of Vgat, which encodes a vesicular GABA transporter, showed an ataxic phenotype that did not coincide with visible brain malformations at 40 weeks of age.…”

Neonatal brain injury causes cerebellar learning deficits and Purkinje cell dysfunction

“…However, some aspects of hypoxic brain injury persist, including dysmaturation of specific neuronal and glial cell populations in both gray and white matter regions of the brain, and disruption of inhibitory gamma-aminobutyric acid (GABA) neurotransmission 20 similar to what is observed in humans 21 . Evidence obtained by multiple laboratories strongly indicates that cerebellar abnormalities result at least in part from defective GABA signaling involving both neurons and glia 22 , 23 in the adult brain. In the developing brain, GABA plays distinct roles including neuronal excitation 24 , 25 and trophic signaling 26 – 28 .…”

Nitric Oxide Synthase and Oxidative Stress Mediating Secondary Neuronal Damage in Perihaematoma Region of Intracerebellar Hemorrhage of Mice

“…They also demonstrated a decrease in GABA on day 1 in lesioned tissue, but not deeper hippocampal tissue, which they proposed was due to decreased conversion of glutamate to GABA that leads to excitotoxicity (Colombel, Lalonde, & Caston, 2002). In another study, they found that changes in receptor containing subunit γ2, a subunit of GABAA receptors in rats at day 7 developed seizures following TBI (Kaja et al, 2015). Our results suggest that there could be a plausible event like this that happens in the ICbH model in mice whereby GABAAα1 receptor containing subunit expression causes a further tip of the balance between excitation to inhibition to become more excitatory, this may also be because GABA's inhibitory effects in the adult brain is known to be reversed to excitatory by pathological conditions such as epilepsy and traumatic brain injury (TBI) (Ben-Ari, 2014).…”

“…GABAA receptors are ionotropic receptors that play a vital role in the inhibition of excitation in the CNS (Enna, 2007). In the cerebellar they form by four types on interneurons activated by granule cells (Kaja et al, 2015). The receptor subunits including α1-6, β1-3, γ1-3 and δ.…”