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

Molecular Psychiatry volume 26, pages 7225–7246 (2021)Cite this article

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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 (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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Fig. 1: Neurocognitive deficits in patients with CACNA1A haploinsufficiency.
Fig. 2: Cacna1a haploinsufficiency in PV-INs reduces synaptic inhibition and leads to decreased anxiety, reversal learning deficits and selective attention deficits.
Fig. 3: Haploinsufficiency of Cacna1a in pyramidal cells does not affect excitatory synaptic transmission in the frontal cortex and does not induce apparent behavioural deficits.
Fig. 4: Selective attention deficits recapitulated by a targeted heterozygous deletion of Cacna1a in the mPFC.
Fig. 5: Cognitive rigidity recapitulated by a targeted heterozygous deletion of Cacna1a in the OFC.
Fig. 6: The chemogenetic activation of PV-INs in the mPFC or OFC respectively rescues the selective attention deficits and the reversal learning deficits in PVCre;Cacna1ac/+ mutants.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to the patients and families for their dedication and support towards our work. We acknowledge Ilse Riebe for preliminary data; J. Waldron, F. Boucher, D. Carrier and the animal facility personnel for their care of animals involved in this study. A. Van den Maagdenberg (U. Leiden), S. Arber (U. Basel) and G. Fishell (NYU, USA) generously donated various mouse lines. This work was supported by the Canadian Institutes for Health Research (CIHR, Grant MOP #119553 and PJT-391422 to ER; PJT-153311 to J-CL), the Fonds de la Recherche du Québec en Santé (FRQS; Groupe de Recherche sur le Système Nerveux Central [GRSNC] group grant, and Centre Interdisciplinaire de Recherche sur le Cerveau et l’Apprentissage [CIRCA] center grant, to J-CL). A. Lupien-Meilleur received MSc/PhD training awards from the CHU Ste-Justine Fondation des Étoiles and from the Department of Neuroscience, Université de Montréal. XJ received a post-doctoral training award from the Savoy Foundation. J-CL is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. ER receives a Clinician-scientist salary award from the Fonds de Recherche du Québec en Santé (FRQS) and a Young Investigator Award from the CIHR.

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Authors and Affiliations

  1. CHU Ste-Justine Research Center, Montreal, QC, Canada

    Alexis Lupien-Meilleur, Xiao Jiang, Mathieu Lachance & Elsa Rossignol

  2. Department of Neurosciences, U. de Montreal, Montreal, QC, Canada

    Alexis Lupien-Meilleur, Xiao Jiang, Jean-Claude Lacaille & Elsa Rossignol

  3. Department of Pediatrics, U. de Montreal, Montreal, QC, Canada

    Vincent Taschereau-Dumouchel, Louise Gagnon, Catherine Vanasse & Elsa Rossignol

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AL-M, ER, and J-CL contributed to the conception and design of the study. AL-M, XJ, VT-D, LG, CV, and IR contributed to data acquisition and analysis. AL-M, XJ, ML, J-CL, and ER contributed to the manuscript preparation and editing. All authors approved the final version of the manuscript.

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Correspondence to Elsa Rossignol.

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Lupien-Meilleur, A., Jiang, X., Lachance, M. et al. Reversing frontal disinhibition rescues behavioural deficits in models of CACNA1A-associated neurodevelopment disorders. Mol Psychiatry 26, 7225–7246 (2021). https://doi.org/10.1038/s41380-021-01175-1

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