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

Cezar M Tigaret,Edward R Morrell,Kerrie L Thomas,Tzu-Ching E Lin,Matthew W Jones,Michael C O’Donovan,Anna L Moon,Lawrence S Wilkinson,Michael J Owen,Jeremy Hall,Lucy Sykes

doi:10.1038/s41380-020-01001-0

Cezar M Tigaret, Edward R Morrell + Show 9 more

Open Access

https://doi.org/10.1038/s41380-020-01001-0

Copy DOI

Journal: Molecular Psychiatry	Publication Date: Feb 17, 2021
Citations: 19	License type: open-access

Affiliation: Cardiff University, University of Bristol

Abstract

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.

Highlights

The major psychiatric disorders such as schizophrenia and bipolar disorder place an enormous burden on society yet have seen little advances in mechanistic understanding and therapy
We investigated the effects of reduced CaV1.2 dosage on associative fear learning using rats hemizygous for a truncating mutation in exon 6 of Cacna1c gene encoding the pore-forming α1C subunit of CaV1.2 L-voltage-gated calcium channels (VGCCs) [33] (“Materials and methods”)
This aberrant learning can be objectivized by the latent inhibition (LI) procedure, which requires hippocampal and mesolimbic dopaminergic functional integrity [18, 37] and is affected in psychosis [17]

Summary

Introduction

The major psychiatric disorders such as schizophrenia and bipolar disorder place an enormous burden on society yet have seen little advances in mechanistic understanding and therapy. May pave the way to new therapeutics [2] Promising in this respect is the demonstration of strong associations of both schizophrenia and bipolar disorder with genetic variations in voltage-gated calcium channels (VGCCs) [3], especially the CACNA1C gene, which encodes the pore-forming α1C subunit of CaV1.2 L-type VGCCs (L-VGCCs) [4, 5]. The association of rare deleterious mutations in genes encoding VGCC subunits, including CACNA1C, with schizophrenia and other neurodevelopmental disorders further supports the view that decreased CACNA1C expression can contribute to disease risk [11, 12]. Understanding the functional effects of CACNA1C dosage, and in particular reduced dosage, is necessary to discerning the contribution of genetic variation in L-VGCCs to neuropsychiatric risk

Methods

Results

Conclusion