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

At some point in our lives, we all are likely to encounter anxiety. Whether it comes in the form of public speaking, precarious heights, or visiting the dentist, these heart-pounding moments can momentarily obstruct our ability to think rationally. Among other unusual behavior predispositions, unrelenting anxiety marks a variety of neuropsychiatric disorders. Commonalities like this led researchers to wonder if there are common links in the brains of people with psychiatric disorders that produce anxiety in addition to the other features of their particular condition. Over the past decade, the gene CACNA1C has emerged as a candidate risk factor for bipolar disorder, schizophrenia, attention deficit hyperactivity disorder, major depression, and autism. Animal models of CACNA1C-deficiency demonstrate its role in anxiety-like behavior. My research aims to determine whether the protein product of CACNA1C, a cellular calcium conduit called Ca_v1.2α1, contributes to the brain changes that occur in people with neuropsychiatric disorders.

Ca_v1.2 α 1 channels calcium into and out of cells in the brain. Calcium works as a messenger in cells that allows them to sense and react to changes within and around them. For example, normal calcium signals from Ca_v1.2 α 1 strengthen communication between neurons and promote energy production to fuel this communication. However, if this precise communication is even slightly out of tune, such as in neuropsychiatric disease, this may disconnect these important signals between and around neurons. My research investigated what signaling pathways Ca_v1.2 α 1 connects within neurons and other brain cells and how its loss might starve communicating neurons of this critical function when they need it most.

To address this goal, I studied mice lacking Cacna1c and Ca_v1.2 α 1 in their brain cells. We discovered that Ca_v1.2 α 1 does not physically interact with mitochondria, one of the major fuel providers of cells. However, loss of Ca_v1.2 α 1 disrupts energy production of brain cells in a way that changes over time and culminates in neuronal damage. Importantly, I also discovered that Ca_v1.2 α 1 is not only important in neurons of the brain, but also plays an unexpected role in the vasculature of the brain through its function in pericyte cells. These pericyte cells regulate brain blood flow and protect the brain from toxic molecules in the blood. Abnormal pericyte activity has recently been shown to increase risk for developing dementia, so Ca_v1.2’s role on these cells may contribute to similar pathways. These new roles of Ca_v1.2 α 1 in brain cell energy production and neuron health help us to understand the basic functions of the brain, as well as how they might go awry in neuropsychiatric disease. In time, these surprising new roles of Ca_v1.2 α 1 in brain health might help develop new treatments for patients suffering from neuropsychiatric disease.