Research Summary Cellular and molecular mechanisms of synapse formation and plasticity in cortical development and disease Research in my laboratory focuses on understanding the cellular and molecular mechanisms of synapse formation, competition, and elimination in the developing visual cortex. The main approach we use is to study the formation, persistence, and elimination of individual synapses between dissociated, cultured visual cortical neurons using time-lapse imaging. This is accomplished by simultaneously imaging the dynamics of pre- and postsynaptic proteins as they are recruited to, stabilized at, or removed from visualized synaptic sites. To complement this cell culture approach, we also use biochemistry, histology, electron microscopy, and whole-cell patch-clamp recording to investigate the cellular and molecular mechanisms that underlie the formation, stabilization, and/or elimination of visual cortical synapses. Specific signals that guide synapse formation and plasticity are studied by manipulating them locally at forming and/or mature synapses. We are also studying the molecular signals that mediate the synapse-specific effects of neuronal activity in strengthening or weakening synapses during activity-dependent competition. Using these approaches, we have discovered that synaptic vesicle proteins (STVs) and NMDA receptors (NRTPs) are trafficked in mobile transport packets in axons and dendrites, respectively, prior to synapse formation. STVs cycle during their transport along axonal membranes and growth cone filopodia and NRTPs undergo a novel form of transport, cycling with the membrane during pauses of movement along microtubules in dendrites. Axodendritic contact leads to bidirectional signaling which causes rapid recruitment of STVs and NRTPs to nascent synapses. Although current models imply that contact initiates signaling cascades that alter the velocity or directionality of synaptic precursors, we recently discovered that synaptogenic molecules instead alter precursor pausing behavior to cause their accumulation at nascent synapses. Moreover, sites of STV pausing are predefined sites for the selective formation of en passant synapses. Finally, both STVs and NRTPs can be recruited to nascent synapses through a novel, direct physical association with transmembrane synaptogenic molecules such as TrkB and neuroligin, respectively. Current research on this topic is focused on elucidating the role of activity, actin, lipid rafts, and intracellular signalign cascades on the recruitment of pre- and postsynaptic proteins to nascent synapses. In addition to studying the cellular and molecular mechanisms of synapse formation and plasticity, we are also interested in elucidating the role for immune molecules in early postnatal cortical development. To that end, we have discovered thet MHC class I molecules negatively regulate the initial establishment of cortical connections. We are now working to identify the role for cytokines and synaptic activity in regulating MHCI expression as well as determining the mechanisms that MHCI uses to negatively regulate cortical connectivity. Since these immune molecules are implicated in several neurodevelopmental disorders, including autism and schizophrenia, MHCI molecules could mediate the effects of the environment on cortical connectivity both during normal development and in neurodevelopmental disorders.