Robert Edwards, MD

The Synaptic Basis of Behavior

    The nervous system encodes information through the timing and frequency of action potentials.  Synapses process this input by determining which features of the firing pattern release neurotransmitter. However, we do not understand the molecular mechanisms responsible for extracting this information, making it difficult to understand the function of neural circuits, their role in behavior and their dysfunction in neuropsychiatric disease.  

We work on several, fundamental questions about the regulation of neurotransmitter release and its consequences for physiology, behavior and disease.
  
1) What tunes neurotransmitter release to different firing frequencies? The high speed of neurotransmitter release enables many synapses to convey precise information about timing, but the resulting depletion of synaptic vesicles limits the response to firing at high frequency.  In contrast, burst firing triggers the phasic dopamine release required for reinforcement learning. What determines the role of a synapse in extracting information about timing versus frequency?  The analysis of neurotransmitter corelease has begun to suggest the cellular mechanisms responsible for these two modes of signaling, and we wish to explore the consequences for neural circuitry and behavior.  

2) What is the normal function of proteins involved in neurodegeneration?  Neural degeneration is associated with the aggregation of characteristic proteins such as -synuclein (in the case of Parkinson’s disease).  We know very little about the normal function of these proteins even though that is the context in which disease originates. Parkinson’s disease involves a dopamine deficiency and synuclein is a presynaptic protein that can inhibit release. We thus wish to understand how the function of synuclein contributes to both symptoms and the underlying degenerative process. 

3) What targets peptides for regulated release?  Dense core vesicles mediate the release of peptide hormones and neural peptides.  The properties of release dictate the time course of signaling and in pancreatic isleet cells, defects underlie type 2 diabetes. However, we know very little about the formation of dense core vesicles and how they acquire the membrane proteins that determine the speed and mode of fusion.  We have identified several components of the machinery required for biogenesis of dense core vesicles.  We now wish to understand how they function to assemble dense core vesicles and the physiological consequences for release.  

4)  How do synaptic vesicles fill with neurotransmitter?  The quantal nature of neurotransmission depends on the regulated exocytosis of synaptic vesicles filled with transmitter.  We have identified several of the proteins that transport neurotransmitters into synaptic vesicles and wish to understand how they coordinate this activity with the rapidly changing conditions that accompany the exo- and endocytic cycling of synaptic vesicles.  We combine structural approaches with biochemistry, imaging and synaptic physiology to understand how the mechanism and regulation of vesicular glutamate transport influences neurotransmission, circuits and neurological disease.
 

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Academic community service and committee membership: NS admissions committee, Chair of NS student advisors/student progress committee