The role of the risk gene CACNA1C in neuroinflammation and peripheral immunity in autism spectrum disorder.

Boller AL; Ruland T; Dantas RL; Michels S; Dannlowski U; Scheu S; Baune BT; Culmsee C; Alferink J

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, restricted and repetitive behaviors and interests, with the severity of symptoms varying greatly among individuals. The pathogenesis of ASD is influenced by the complex interaction of genetic and environmental factors. Increasing evidence suggests that dysregulated immune processes represent a crucial aspect in ASD pathology. The CACNA1C gene, which encodes the pore-forming α1C subunit of the L-type calcium channel (LTCC) CaV1.2, is a major genetic risk factor for ASD. CaV1.2 channels modulate neuronal excitability, synaptic plasticity, and neurotransmitter release in the central nervous system (CNS), all of which are essential for brain development and function. CaV1.2 channels are also expressed in generally non-excitable immune cells, including CNS microglia and peripheral immune cells, where they influence activation, differentiation, and cytokine release. These immune functions may contribute to ASD pathogenesis; however, the specific role of CaV1.2 in immune regulation and neuroinflammation in ASD is yet to be elucidated. Here, we will review recent research on the role of CACNA1C in immune mechanisms relevant to ASD. We will summarize current knowledge on the function of CaV1.2 in brain microglia and peripheral immune cells such as T cells, B cells, and dendritic cells that contribute to immune dysfunction in ASD. In addition, we will discuss the therapeutic prospects of targeting CaV1.2 channels in immune cells to manage both behavioral and inflammatory conditions associated with ASD.