RESEARCH

Discovering the molecular mechanisms for short-term plasticity

Presynaptic calcium signals regulate nearly all forms of short-term plasticity. Identifying the molecular calcium sensors that drive short-term plasticity is a crucial step towards understanding how neural circuits use short-term plasticity to perform computations. We recently discovered that a prominent form of short-term plasticity called “facilitation” is driven by the high-affinity calcium sensor synaptotagmin-7 (Syt7). There are 17 members of the synaptotagmin family that can bind to lipid membranes and synaptic proteins, and many other calcium–binding proteins of unknown function have been identified as structurally similar to synaptotagmin, suggesting they may also regulate neurotransmitter release. We manipulate the expression of these proteins, and use electrophysiology and imaging to discover the mechanisms of short-term plasticity.

THE IMPACT OF SHORT-TERM PLASTICITY ON NEURAL CIRCUIT FUNCTION

To understand how short-term plasticity shapes circuit activity, we use optical techniques to monitor the activity of hundreds of neurons in vivo while mice engage in engage in behaviors. Recent studies have shown that neuronal ensembles synchronize their activity, and that synchrony is required for short-term memory and decision making. Models suggest that facilitation underlies this synchrony. We are testing whether genetic perturbations of short-term plasticity lead to a loss of synchronous activity. To guide our experiments and interpret our results, we model artificial neural networks and and without short-term plasticity, and assess network dynamics and information storage.

HOW DOES SHORT-TERM PLASTICITY AFFECT SENSORY AND COGNITIVE PROCESSING?

Our primary goal in discovering the mechanisms of short-term plasticity is to be able to manipulate synapses in vivo and determine how synaptic plasticity regulates the neural circuits that drive behavior. The discovery that synaptotagmin 7 mediates facilitation at most synapses in the mammalian brain allows to perform the first experiments designed to link short-term plasticity to behavior. We use a wide array of behavioral assays to evaluate cognitive and sensory processing in Syt7 knockout mice.