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Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c

Tigaret, Cezar M. ORCID:, Tzu-Ching, E. Lin, Morrell, Edward R., Sykes, Lucy, Moon, Anna L. ORCID:, O'Donovan, Michael ORCID:, Owen, Michael J. ORCID:, Wilkinson, Lawrence S. ORCID:, Jones, Matthew W., Thomas, Kerrie L. ORCID: and Hall, Jeremy ORCID: 2021. Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c. Molecular Psychiatry 26 , pp. 1748-1760. 10.1038/s41380-020-01001-0

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Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of mutations of one copy of Cacna1c on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbour marked impairments in learning to disregard non-salient stimuli, a behavioural change previously associated with psychosis. This behavioural deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signalling in dendritic spines and decreased signalling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small-molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioural and synaptic plasticity deficits in Cacna1c+/− rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signalling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signalling pathways with BDNF mimetic drugs as a genetically informed therapeutic approach for rescuing behavioural abnormalities in psychiatric disorder.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Springer Nature
ISSN: 1359-4184
Date of First Compliant Deposit: 18 January 2021
Date of Acceptance: 1 December 2020
Last Modified: 11 Oct 2023 17:41

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