From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

Abstract

The L-type calcium channels (LTCCs) Ca1.2 and Ca1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Ca1.2 and Ca1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca1.2- and Ca1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons

“…Of the multiple classes of Ca v channels, Ca v 1 L-type channels are key mediators of Ca 2+ signals controlling neurogenesis (Marschallinger et al, 2015; Temme et al, 2016; Volkening et al, 2017), neurite growth (Audesirk et al, 1990; Robson and Burgoyne, 1989; Roehm et al, 2008; Schindelholz and Reber, 2000), and gene transcription (Dolmetsch et al, 2001; Graef et al, 1999; Oliveria et al, 2007). Mutations affecting the major Ca v 1 channels in the brain, Ca v 1.2 and Ca v 1.3, are linked to a variety of neurological and psychiatric disorders (Kabir et al, 2017; Pinggera and Striessnig, 2016). Thus, factors that regulate Ca v 1 channels may be critical for maintaining the balance between normal and diseased states of the nervous system.…”

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

“…Over the last few years, several studies have identified common single polymorphisms (SNPs) in calcium voltage-gated channel subunit alpha 1C (CACNA1C) and ankyrin-3 (ANK3) in BD patients, implicating these as susceptibility genes for BD [42,43] depletion and are critical for normal brain development and plasticity [44,45] and ankyrin directly interacts with the ER 1,4,5-inositol triphosphate receptor (IP3R), which is localized at MAMs and is responsible for ER Ca 2+ release [46]. Carriers of the CACNA1C risk polymorphism rs1006737 exhibit greater age-related thickness of cortical brain areas widely associated with mood regulation in BD [47].…”

Regulation of the Expression of the Psychiatric Risk Gene <b><i>Cacna1c</i></b> during Associative Learning

“…L-type VGCCs are known to play a central role in controlling activity-dependent synaptic plasticity [15-17]. Ca v 1.2 channels, the predominant form of L-type VGCCs in the mammalian brain, are ideally situated somato-dendritically to link neuronal activation to calcium signalling and the regulation of gene expression [15, 16].…”