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. 2021 Dec;26(12):7225-7246.
doi: 10.1038/s41380-021-01175-1. Epub 2021 Jun 14.

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

Alexis Lupien-Meilleur  1   2 , Xiao Jiang  1   2 , Mathieu Lachance  1 , Vincent Taschereau-Dumouchel  3 , Louise Gagnon  3 , Catherine Vanasse  3 , Jean-Claude Lacaille  2 , Elsa Rossignol  4   5   6
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Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders

Alexis Lupien-Meilleur et al. Mol Psychiatry. 2021 Dec.

Abstract

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.

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References

    1. Rajakulendran S, Kaski D, Hanna MG. Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol. 2012;8:86–96. - PubMed - DOI
    1. Damaj L, Lupien-Meilleur A, Lortie A, Riou E, Ospina LH, Gagnon L, et al. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Eur J Hum Genet. 2015;23:1505–12. - PubMed - PMC - DOI
    1. Epi KC. De novo mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet. 2016;99:287–98. - DOI
    1. Auvin S, Holder-Espinasse M, Lamblin MD, Andrieux J. Array-CGH detection of a de novo 0.7-Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia. 2009;50:2501–03. - PubMed - DOI
    1. Reinson K, Oiglane-Shlik E, Talvik I, Vaher U, Ounapuu A, Ennok M, et al. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. Am J Med Genet A. 2016;170:2173–6. - PubMed - DOI

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