Cell-specific consequences of CAv1.2 loss on brain health

Mental illness restricts major life activities of one in five United States adults and comprises one fourth of disease burden globally. While current medications alleviate some symptoms endured by patients with mental illness, significant treatment gaps persist. This gap is in large part due to the elusive underlying molecular and biochemical pathophysiology of neuropsychiatric disease. To better understand the causes of neuropsychiatric disease, researchers searched for correlated genetic risk loci in the largest genome-wide association study to date. Through these efforts, significant risk loci were identified in the CACNA1C gene among people with bipolar disorder, schizophrenia, major depression, attention deficit-hyperactivity disorder, and autism spectrum disorder. CACNA1C encodes Cav1.2, the predominant pore-forming L-type voltage-gated calcium channel (LTCC) subunit in the brain. While Cav1.2 is well-characterized for its role in normal synaptic transmission in mice, there is a critical need to learn how Cav1.2 function might underlie psychiatric disease. Thus, we investigated the role of Cav1.2 in global brain health by focusing on neuronal death, a critical component of many forms of neuropsychiatric disease.Previously, we identified impaired survival of young hippocampal neurons in the dentate gyrus of the hippocampus in forebrain-specific Cav1.2 knockout mice. The mechanism by which Cav1.2-deficiency contributes to neuronal cell death, however, was unknown. The long-term goal of this project was to understand molecular pathways involved in normal and pathological Cav1.2 activity in order to aid the development of novel, mechanism-based treatments for neuropsychiatric disorders related to neuron death. The initial overall goal was to understand Cav1.2’s role in neuronal survival. Because dysregulated mitochondrial calcium homeostasis predisposes neurons to apoptosis, we hypothesized that normal Cav1.2 activity mediates mitochondrial calcium dynamics, preserving metabolic state, while anomalous Cav1.2 signaling primes neurons for apoptosis. Through brain mitochondria protein characterization, neurovascular integrity assessment, and metabolomic adaptation analysis, I broadly illustrate novel roles for Cav1.2 in maintaining brain health.