Abstracts

Rationale: Loss-of-function mutations in the CACNA1A gene, which encodes the α1 subunit of voltage-gated Ca_V2.1 channels, result in episodic ataxia (EA2) and epilepsy in humans. These conditions are rarely associated with overt cognitive deficits. We investigated 15 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, that includes a spectrum of inattention, impulsivity, learning difficulties, working memory deficits, intellectual deficiency and autism. We recently demonstrated that a targeted deletion of Cacna1a causing an ablation of voltage-gated Ca_V2.1 Ca²⁺ channels selectively in forebrain GABAergic interneurons (INs) in mice leads to 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 contribute to the cognitive deficits observed. Methods: To better understand the pathological mechanisms underlying these cognitive deficits, we studied the effects of Ca_V2.1 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 telencephalic PV neuronal populations (PV^cre;Cacna1a^c/+), which targets cortical PV-INs post-natally. Using an optogenetic approach (AAV-ChR2) to selectively activate PV-INs while recording inhibitory post-synaptic events (IPSCs) in orbitofrontal pyramidal cells (PC), we demonstrated that this selective mutation significantly impairs perisomatic inhibition of PC in the orbitofrontal cortex. We assessed the behavioural and cognitive abilities of these mutant mice in the Open Field, the Elevated Plus Maze, the T-maze, the Morris Water Maze and the Reversal Learning Task. Results: These investigations revealed that the haploinsufficiency of Cacna1a in PV-INs leads to impulsivity, impaired working memory and reduced cognitive flexibility (impaired reversal learning) in PV^cre;Cacna1a^c/+ mutant mice. These deficits could be partly recapitulated by local AAV-Cre injections in the orbitofrontal cortex of Cacna1a^c/+ mice. Conclusions: Our results demonstrate that haploinsufficiency of Cacna1a leads to significant cognitive and behavioural impairment in humans and in conditional mutant mice, and that this is partly attributable to disrupted perisomatic inhibition in orbitofrontal circuits.