L-type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes

Abstract

Brain Ca_v 1.2 and Ca_v 1.3 L-type Ca²⁺ channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Ca_v 1.2 and Ca_v 1.3 Ca²⁺ signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour-based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice.

Figure 1

Schematic diagram of the L‐type Ca²⁺ channels Ca_v1.2 and Ca_v1.3, and β and α2δ auxiliary subunits

Figure 2. Overlapping neurocircuitry of L‐type Ca²⁺ channels contributing to endophenotypes of psychiatric disorders

Single arrow denotes unidirectional connectivity in the direction of the arrow and double arrow denotes bidirectional connectivity. PFC, prefrontal cortex; HPC, hippocampus; STR, striatum; NAc, nucleus accumbens; AMG, amygdala; VTA, ventral tegmental area.