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

Abstract

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, 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 Ca_v1.2 and Ca_v1.3. 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 Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

Keywords: Addiction; CACNA1C; CACNA1D; Cav1.2; Cav1.3; Mood; Social.

Fig. 1

Ca_v1.2- and Ca_v1.3-mediated anatomical and molecular pathways underlying the endophenotypes associated with neuropsychiatric disorders. Solid lines indicate pathways that have been identified for the respective behavioral endophenotypes and dotted lines indicate potential pathways that may be recruited AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; PFC = prefrontal cortex; HPC = hippocampus; NAc = nucleus accumbens; VTA = ventral tegmental area; REDD1 = regulated in development and DNA damage response 1; CP-AMPAR = Ca²⁺-permeable AMPAR; ERK2 = extracellular regulated kinase 2; CaMKII = CaM-dependent protein kinase II

Fig. 2

Ca_v1.2 and Ca_v1.3 signaling mechanisms. Solid lines indicate pathways that have been directly linked to Ca_v1.2 or Ca_v1.3 channels and dotted line indicates potential pathway that may be recruited. Black arrows indicate Ca_v1.2-specific pathways; red arrows indicate Ca_v1.3-specific pathways. mTORC1 = mammalian target of rapamycin complex 1; REDD1 = regulated in development and DNA damage response 1; P-MAPK = phosphorylated mitogen-activated protein kinase; P-CaMK = phosphorylated CAM-dependent protein kinase; P-eIF2α = phosphorylated eukaryotic initiation factor 2 alpha; CaN = calcineurin; P-Akt = phosphorylated protein kinase B; MEF2 = myocyte enhancer factor 2; NFAT = nuclear factor of activated T cells; P-CREB = phosphorylated cAMP response element-binding protein

Fig. 3

Proposed mechanistic model for ventral tegmental area (VTA) Ca_v1.3 activation, which leads to depressive-like and cocaine-related behaviors. VTA Ca_v1.3 channel activation by BayK 8644 promotes CAM-dependent protein kinase (CaMK)II/extracellular regulated kinase (ERK)/ cAMP response element-binding protein (CREB) signaling, which results in the production of the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Subsequently, BDNF gets transported from the VTA to the nucleus accumbens (NAc), which may mediate both depressive-like and cocaine behaviors, via increase in Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs). We propose that depressive like-behavior is mediated by a BDNF/tropomyosin receptor kinase B (TrkB) mechanism in NAc dopamine (DA) D1 receptor-expressing cells [350] and cocaine-related behaviors in NAc DA D2 receptor-expressing cells [351]