Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders

CACNA1A deletions cause epilepsy, ataxia, and a range of neurocognitive deficits, including inattention, impulsivity, intellectual deficiency and autism. To investigate the underlying mechanisms, we generated mice carrying a targeted Cacna1a deletion restricted to parvalbumin-expressing (PV) neurons (PVCre;Cacna1ac/+) or to cortical pyramidal cells (PC) (Emx1Cre;Cacna1ac/+). GABA release from PV-expressing GABAergic interneurons (PV-INs) is reduced in PVCre;Cacna1ac/+ mutants, resulting in impulsivity, cognitive rigidity and inattention. By contrast, the deletion of Cacna1a in PCs does not impact cortical excitability or behaviour in Emx1Cre;Cacna1ac/+ mutants. A targeted Cacna1a deletion in the orbitofrontal cortex (OFC) results in reversal learning deficits while a medial prefrontal cortex (mPFC) deletion impairs selective attention. These deficits can be rescued by the selective chemogenetic activation of cortical PV-INs in the OFC or mPFC of PVCre;Cacna1ac/+ mutants. Thus, Cacna1a haploinsufficiency disrupts perisomatic inhibition in frontal cortical circuits, leading to a range of potentially reversible neurocognitive deficits.