Investigation de l'implication des neurones GABAergiques exprimant la parvalbumine dans les déficits cognitifs associés aux délétions du gène Cacna1a
Loss-of-function mutations in the CACNA1A gene, which encodes the α1 subunit of voltage-gated CaV2.1 channels, result in episodic ataxia (EA2) and epilepsy in humans. These conditions are rarely associated with overt cognitive deficits. We recently investigated 16 patients from 4 non-consanguinous families carrying different CACNA1A loss-of-function mutations and revealed that the majority of them had moderate to significant neurocognitive impairment. Targeted deletion of Cacna1a selective to forebrain GABAergic interneurons (INs) in mice leads to a selective synaptic impairment of parvalbumin-positive (PV) fast-spiking basket cells that is sufficient to induce generalised epilepsy. We therefore, propose that a selective impairment of perisomatic inhibition resulting from PV-INs synaptic dysfunction in neocortical orbitofrontal circuits might also contribute to the cognitive deficits associated with Cacna1a deletions. In this study, we examined the effects of CaV2.1 channel ablation in PV neurons that are thought to be critical for cognition. To this end, we generated mutant mice carrying a targeted heterozygous Cacna1a deletion restricted to PV neuronal populations (PVcre; Cacna1ac/+); this mutation occurs post-natally. Using an electrophysiologic approach combined with optogenetics, we demonstrated that this selective mutation significantly impairs perisomatic inhibition of pyramidal cells in the orbitofrontal cortex. We assessed the behavioral and cognitive abilities of these mutants with different behavioral tests and discovered that they present impulsivity and reduced cognitive flexibility.  In conclusion, our work suggests that loss-of-function mutations in Cacna1a are associated with cognitive impairments, which are partly attributable to disrupted perisomatic inhibition in orbitofrontal circuits.
CACNA1A EA2 Interneurons Cav2.1 Cognition