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

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.

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

“…We have demonstrated in this study that the compensatory mechanisms affecting neuronal excitability can be ameliorated pharmacologically with the administration of selective agonists such as 77-LH-28-1 rescuing impairments in synaptic integration and plasticity, a proof of principle that may be applicable to other psychiatric disorder risk variants. For example, an increase in input resistance due to the administration of 77-LH-28-1 could facilitate spike backpropagation, potentially rescuing the plasticity impairment reported in the Cacna1c+/model of genetic vulnerability to schizophrenia (76). Highly selective muscarinic M1 receptor agonists have efficacy clinically with negligible side effects(77-80) making them attractive pharmaceutical tools.…”

A critical review of zebrafish schizophrenia models: Time for validation?

“…Albeit discordant results sometimes, there are lower levels of BDNF in both medicated and nonmedicated SCZ patients when compared to controls (Favalli et al, 2012). Previous studies have found deficits in the levels of Bdnf in mice harbouring forebrain-specific conditional knockout of Cacna1c (Lee et al, 2016), the prefrontal cortex of both CaV1.2 haploinsufficient rats ( ) and persons with CACNA1C risk-associated genetic variants upon analysis of the BRAINEAC data (Sykes et al, 2019;Tigaret et al, 2021). Indeed, BDNF is associated with synaptic transmission and neural plasticity (Carvalho et al, 2008;55 Gottmann, Mittmann and Lessmann, 2009;Favalli et al, 2012).…”

Functional characterisation of single nucleotide variants of the psychiatric risk gene cacna1c in the zebrafish

“…In addition, missense mutations in exons 8 or 8a of CACNA1C cause a rare subtype of ASD called Timothy syndrome 1 via a gain-of-function (GOF) mechanism [9,18]. Thus, there is a large interest in characterising the consequences of CACNA1C aberrations, as recently illustrated [19].…”

“…Most of the functional roles of CaV1.2 in psychiatric disorders have been obtained from genetic rodent models [9,19] and to a lesser extent using zebrafish genetic models [22,23]. Except for a recent aforementioned study [23], the role of cacna1c within the context of normal brain function, behaviour, and disease in zebrafish, has been underexplored.…”

“…Timothy syndrome 1 via a gain-of-function (GOF) mechanism [9,18]. Thus, there is a large interest in characterising the consequences of CACNA1C aberrations, as recently illustrated [19].…”