The effects of synaptically released zinc on neuronal processing and brain function

West Virginia University, Morgantown WV

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Abstract

Project Abstract Many regions of the brain including the cortex, hippocampus, basal ganglia, and limbic structures are highly enriched with synaptic zinc. Synaptic zinc (as Zn2+) is loaded into presynaptic vesicles by zinc transporter 3 (ZnT3), where it is coreleased with glutamate during synaptic transmission. Synaptic zinc can modulate many fundamental aspects of synaptic signaling. ZnT3 KO mice (which lack synaptic zinc) display a range of cognitive and sensory impairments and demonstrate behavioral deficits associated with autism and schizophrenia. Mounting evidence from human populations shows that mutations in certain zinc transporters are linked with major neurological disorders such as schizophrenia. Together, these findings strongly suggest that synaptic zinc signaling is important for neuronal processing. Our laboratory is focused on understanding how brain-specific zinc transporter proteins control zinc release and clearance at synaptic terminals, how different types of brain cells utilize zinc during synaptic transmission, and how the effects of zinc regulate the activity and structure of individual synaptic connections in the brain. Together these approaches will allow us to answer fundamental questions concerning the role of synaptic zinc in brain function and provide new mechanistic insights into endogenous mechanisms that shape synaptic and neural processing. The overall vision for project over the next five years is to understand the dynamics of endogenous synaptic zinc in the brain: how it is released, how it is cleared, how it interacts with pre- and postsynaptic receptors, how it supports synaptic structure, and how it is regulated by zinc transporter proteins. Because zinc is a fundamental aspect of cellular function, understanding the mechanisms underlying its actions at synapses will not only improve our understanding of cellular processes important in the brain, but will also pave the way toward new targets in the treatment of pathological conditions.