College of Arts and Science
Among the processes that govern synaptic development and refinement to build the adult nervous system, synaptic maturation is an essential series of events that promotes the transition from nascent, weak synapse to robust, reliable connection. In the absence of appropriate synaptic maturation, weakened synapses persist into adulthood and their presence can underlie neurodevelopmental, neuropsychiatric, and perhaps even neurodegenerative diseases. Despite the importance of this process to normal neurodevelopment, the molecular mechanisms that underlie, and even the precise events comprising, synaptic maturation remain incompletely understood. By studying both central and peripheral synapses in Drosophila, we have uncovered that a distinct set of events constitutes synaptic maturation at NMJ versus olfactory synapses. NMJ synapse maturation is governed by the recruitment of postsynaptic scaffolding and cytoskeletal proteins following initial presynaptic outgrowth and acquisition of a robust behavioral output. Olfactory synapse development is instead governed by the establishment of a mature complement of active zones made by a class of neurons following glomerular neurite growth. We have characterized the events of synaptic maturation in both the CNS and the PNS and began to determine the molecular cascades that influence synaptic maturation. At the NMJ, we have found that multiple cell surface proteins, including the Alzheimer's Disease-linked proteolytic complex, gamma-secretase, influence synaptic maturation. Gamma-secretase functions in a non-canonical Wnt pathway to regulate expression of genes associated with synaptic maturation. In the CNS, distinct Alzheimer's-disease linked and cancer-linked cell surface proteins also influence maturation of glomerular circuits and synaptic growth. In characterizing the events of, and molecules promoting, synaptic maturation, the molecular connections between disease-linked genes and basic developmental processes are becoming evident, suggesting that failures in neurodevelopment may precede and influence neurodegenerative events.
Dr. Timothy J. Mosca
Department of Neuroscience
Vickie & Jack Farber Institute for Neurosciences
Thomas Jefferson University