Synapse-specific effects of synaptically released zinc: implications for auditory processing

Project Summary
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. Since synaptic
zinc inhibits AMPA and NMDA receptors – which mediate the majority of excitatory glutamatergic
transmission in the brain – synaptic zinc can modulate excitatory 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. The goals of this project are to understand how synaptic zinc contributes to normal
neuronal function and how disruptions in zinc signaling are linked to pathological neuronal conditions.
We will take three complimentary experimental approaches to these questions. 1) Using ex vivo brain
slice preparations and optogenetic stimulation paradigms, we dissect the roles of synaptic zinc in shaping
the dynamics of synaptic transmission at specific synaptic connections in cortical microcircuits. 2) Using
in vivo 2-photon calcium imaging, we assess the roles of synaptic zinc in shaping the sensory-evoked
responses of specific classes of auditory cortical neurons in awake mice. 3) Using in vitro high-throughput
screening assays and rational compound design approaches, we are designing novel tools to modulate
the function of specific zinc transport proteins. 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.

Grant Number: 3R35GM138023-05S1
NIH Institute/Center: NIH
Principal Investigator: CHARLES ANDERSON