Dendritic complexity regulation by phospho-S1928 of CaV1.2

Proper brain function is ensured by establishing proper connections between groups of neurons via synapses. Synapses are placed along the dendrites and there they receive and integrate incoming information from input neuron. The size and the morphology of the dendritic tree of the receiving neuron are instrumental to establish proper neuronal circuitry and ensure proper brain function. As shown by several congenital psychiatric diseases, aberrant dendritic morphology results in misplaced, reduced or redundant synaptic connections, hence altering correct brain physiology. L-type voltage gated calcium channels (L-VGCCs) are involved in regulation of dendritic morphology. Several studies outlined the complexity of this regulation, which could be either inhibitory or excitatory. However, the underlying molecular regulation is still not completely understood. In our preliminary results we found that molecular mimicking of phosphorylation on serine 1928 of the CaV1.2 isoform L-VGCCs decreases the length and the branching of the dendritic tree. Conversely, neurons expressing phospho-resistant mutants exhibit an increase of both parameters. In this project we plan to use a combination of fluorescence imaging tools, electrophysiology and transgenic mice to understand how phosphorylation of CaV1.2 regulates the size of the dendritic tree. Our findings will provide essential information on how the neuronal circuitry is established and, therefore, will provide important information on how the brain processes information.

Proper brain activity relies on the ability of neurons to form functional networks that enable the processing of information derived from experience, as well as from emotional and intellectual activity. This flow of information depends on the high degree of specialization of neuronal structures. Neurons, in fact, possess an extensive dendritic arbor: elongated projections emerging from the cell body that are responsible for receiving inputs from neighboring cells. The CaV1.2 class of voltage-gated calcium channels regulates dendritic growth through complex molecular and cellular mechanisms that remain largely unexplored. In our project, we investigated how the regulation of channel function influences the development of the dendritic tree. We found that basal CaV1.2 channel activity is essential for proper dendritic growth. However, enhancing channel activity-either through agonists or adrenergic stimulation-can lead to two distinct outcomes: stabilization of the dendritic arbor without further growth, or promotion of dendritic tree extension. The former occurs when channel availability is normal or increased, while the latter is observed when channel expression is reduced. Thus, the shaping of dendritic arbor structure by L-type voltage-gated calcium channels depends on the coordinated interplay between channel activity and expression levels. Under these conditions, channels can differentially couple to the dendritic growth-inhibiting signaling molecule CaMKII, resulting in a highly variable spectrum of dendritic growth patterns. Altogether, our findings reveal a novel mechanism by which calcium channels control neuronal architecture. This study may provide valuable insights for developing therapeutic strategies targeting neurological and psychiatric disorders characterized by abnormal neurodevelopment and dysregulation of CaV1.2 channel function or expression.