Synapse Development and Function in Mammalian Central Nervous System

Individual neurons connect into functional circuits via synapses, asymmetrical cellular junctions that transmit signals with remarkable speed and precision. The ability of neurons to change the efficacy of synaptic transmission in response to external sensory stimuli is critical for our abilities to learn, remember, and produce behavioral responses. We are interested in understanding how synapses form and operate in normal mammalian brain, and how deficits in synaptic transmission and plasticity translate into cognitive abnormalities. The current research in our laboratory is focused on dissecting the membrane trafficking pathways controlling fast release of chemical neurotransmitters and secretion of soluble factors that modulate synaptic function. Our goals are to define the molecular architecture of synaptic secretory organelles, to elucidate the mechanisms regulating their intracellular trafficking and exocytosis, and to determine how experience-dependent changes in synaptic secretion impact the neural circuits in cortex and hippocampus. A second major direction in the lab is to elucidate the mechanisms governing synaptic integration. The ultimate challenge of regenerative medicine is to develop new treatments for replacement of human neurons that were lost or permanently damaged due to physical injury or illness. The promise of induced pluripotent stem (iPS) cells is based on their capacity to form different cell types, which potentially enables autologous implantation treatments. However it is still unclear which neuron subtypes can be derived from iPS cells, which genes define neuronal identity during stem cell differentiation, and whether these neurons are capable of forming fully functional synapses and integrating into existing circuits. To address these questions, our laboratory is using a multidisciplinary approach that combines genetic, biochemical, optical, and electrophysiological methods.