Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c
Year: 2021
Type: article
Abstract: Genetic variation in CACNA1C , which encodes the alpha-1 subunit of Ca V 1.2 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 altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca 2+ signaling in dendritic spines and decreased signaling 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 behavioral and synaptic plasticity deficits in Cacna1c +/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder. One Sentence Summary Neurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.
Source: Molecular Psychiatry
Institutions: Cardiff University, University of Bristol, Novo Nordisk (India)
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Awards: DEFINE - Defining endophenotypes from integrated neurosciences, G2334658083, Decoding neural assemblies over multiple brain regions, extended experience and sleep-wake cycles, Decoding neural assemblies over multiple brain regions, extended experience and sleep-wake cycles, G3930120097, G4405462294, Investigating genetic and environmental risk for psychosis mediated through L-Type voltage gated calcium channels, Cardiff Integrative Neuroscience 2007, DEFINE - Defining endophenotypes from integrated neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, G5953459058, G6680420078, The role of MlR137 and its targets in associative learning.
OpenAlex ID: W3130009767