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Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders.
- Source :
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Molecular psychiatry [Mol Psychiatry] 2021 Dec; Vol. 26 (12), pp. 7225-7246. Date of Electronic Publication: 2021 Jun 14. - Publication Year :
- 2021
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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 (PV <superscript>Cre</superscript> ;Cacna1a <superscript>c/+</superscript> ) or to cortical pyramidal cells (PC) (Emx1 <superscript>Cre</superscript> ;Cacna1a <superscript>c/+</superscript> ). GABA release from PV-expressing GABAergic interneurons (PV-INs) is reduced in PV <superscript>Cre</superscript> ;Cacna1a <superscript>c/+</superscript> mutants, resulting in impulsivity, cognitive rigidity and inattention. By contrast, the deletion of Cacna1a in PCs does not impact cortical excitability or behaviour in Emx1 <superscript>Cre</superscript> ;Cacna1a <superscript>c/+</superscript> 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 PV <superscript>Cre</superscript> ;Cacna1a <superscript>c/+</superscript> mutants. Thus, Cacna1a haploinsufficiency disrupts perisomatic inhibition in frontal cortical circuits, leading to a range of potentially reversible neurocognitive deficits.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 26
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 34127816
- Full Text :
- https://doi.org/10.1038/s41380-021-01175-1