Proposal Summary/Abstract Neural circuits undergo neurite outgrowth in response to seizures, leading to aberrant axonal sprouting and changes to the morphology and connectivity of mature neurons. Thus, neurite growth inhibitory factors could have clinical applications. Only about one third of patients with epilepsy can control seizures using current antiepileptic drugs, so identification of new therapeutic targets is crucial, yet challenging, since neurite formation remains poorly understood. Here, we propose a function for plexin domain containing 1 (Plxdc1) in regulating neurite initiation and elongation via the potentially downstream kinases Akt and FAK. Plxdc1 is a single transmembrane domain receptor embedded in the plasma membrane and its downstream signaling pathway is currently unknown. Previously, microRNA targeting Plxdc1 has been shown to be inversely correlated with epileptogenesis. Plxdc1 serves as a receptor for nidogen-1 and PEDF. Disruption of nidogen-1 leads to seizure-like symptoms, while deletion of PEDF may contribute to the etiology of Miller-Dieker Syndrome, which is strongly associated with epilepsy. Interestingly, we observed that Plxdc1 overexpression (OE) drives the formation of neurite-like extensions in N2a cells. Plxdc1 OE in primary cortical neurons led to increased dendrite length, while Plxdc1 knockdown led to fewer and shorter dendrites. We confirmed these phenotypes in vivo by using in utero electroporation. We conducted a high-throughput kinase inhibitor library screening in which N2a cells undergoing Plxdc1-OE-driven neurite formation were treated with 493 kinase inhibitors. Based on an initial analysis of results, we hypothesize that Plxdc1 signals via the downstream kinases Akt and FAK to modulate neurite initiation and elongation. Since cytoskeletal dynamics drive the morphological changes that occur during neurite formation, we will investigate how Plxdc1 signaling regulates actin aggregation and microtubule stability. This work will advance our understanding of a fundamental process in normal brain development and may have implications for therapeutic roles in treating epilepsy. Further work is necessary to determine how changes in Plxdc1 expression impact neuronal connectivity and networks.