[R35] The effects of synaptically released zinc on neuronal processing and brain function
Ente: National Institute of General Medical Sciences
Scadenza: 2030-07-31
Importo max: 618.864 EUR
Paese: US
Descrizione
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.
Istituzione: WEST VIRGINIA UNIVERSITY
PI: CHARLES ANDERSON
Progetto: 5R35GM138023-07
Settori: National Institute of General Medical Sciences
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