In all nervous systems, from invertebrates to humans, newly formed synaptic connections are not yet optimally functional. All synapses must undergo a process of synaptic maturation to transition from structurally simple and functionally unrefined connections to structurally complex connections capable of robust synaptic transmission and plasticity. This process is critically important, as failures in synaptic maturation have a marked bearing in health and disease, underlying neurodevelopmental disorders like autism and epilepsy and intellectual disabilities like schizophrenia. Recent work has even suggested that the maturation process may also be hijacked in neurodegenerative diseases like Alzheimer’s. Despite this importance, the molecular mechanisms that underlie synaptic maturation remain poorly understood. Structural events including the recruitment of postsynaptic proteins to nascent presynaptic terminals must preface functional maturation, but even our understanding of the genes and pathways that enable these events remains incomplete. Specifically, the presynaptic receptors involved in maturation remain woefully understudied and there are still critical gaps in our understanding of how established maturation signals are processed postsynaptically to promote development. The long-term goal of this proposal is to identify the molecules that ensure normal synaptic maturation and determine the mechanisms by which they function. To understand these fundamental events, we will use a combination of genetics, high-resolution imaging, and biochemistry approaches to investigate the mechanisms that underlie synaptic maturation. Our preliminary work has identified three transmembrane proteins that likely function in structural synaptic maturation. Mutations in these genes have been associated with early-onset Alzheimer’s disease, failures in neuronal differentiation, and amyotrophic lateral sclerosis, underscoring their importance in a normally functioning nervous system. We will first characterize how each of these molecules contributes to synaptic growth and maturation. Following, we will determine where these genes are expressed and whether they function presynaptically or postsynaptically to mediate synaptic maturation. Finally, we will begin to determine the mechanism by which these genes function and intersect with established signaling pathways that regulate synaptic maturation and development. We expect that this work will first identify new genes that function pre- and postsynaptically to ensure synaptic maturation and second, the mechanisms by which they achieve this goal. With a deeper understanding of the normal function of these genes, we can better understand how they work to stave off disorders like Alzheimer’s disease when present and how mutations in those genes can contribute to the progression of neurodegenerative diseases. In so doing, we will establish a fundamental foundation for the cellular events underlying maturation and begin to inform how impaired synaptic maturation can underlie neurodevelopmental disorders, intellectual disabilities, and neurodegenerative diseases.

PROJECT NARRATIVE Synaptic connections do not optimally function as soon as they form; they must undergo a process of maturation that involves structural growth and functional refinement before they can work properly. Though maturation is essential, and its failure results in neurodevelopmental disorders and intellectual disabilities like autism, schizophrenia, and even Alzheimer's disease, the molecular mechanisms responsible for normal maturation are poorly understood. This work will lead to a deeper understanding of how synapses mature and in so doing, inform better ameliorative treatments for combatting neurological disorders where maturation fails.