Author ORCID Identifier

https://orcid.org/0000-0003-0888-5600

Semester

Summer

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

Kevin Daly

Committee Co-Chair

Ariel Agmon

Committee Member

Ariel Agmon

Committee Member

Eric Horstick

Committee Member

Gary Marsat

Committee Member

Charles Anderson

Abstract

Synaptic zinc signaling modulates synaptic activity and is present in specific populations of cortical neurons, suggesting that synaptic zinc contributes to the diversity of intracortical synaptic microcircuits and their functional specificity. The pool of chelatable synaptic zinc is controlled by the zinc transport protein ZnT3, a protein which functions by moving free zinc into glutamatergic presynaptic vesicles, from which it is co-released with glutamate during synaptic transmission. Once synaptic zinc is released within the synaptic cleft, it acts on glutamate receptors on the post-synaptic spine, including ionotropic NMDA and AMPA receptors. While the inhibitory function of zinc on NMDA receptors is well-characterized, the nature of zinc’s modulatory effect on AMPA receptors is less well-known, with long-standing controversy in the field as to what specific roles zinc signaling plays in AMPA receptor function. To understand the role of zinc signaling in the cortex, we performed whole-cell patch-clamp recordings from intratelencephalic (IT)-type neurons and pyramidal tract (PT)-type neurons in layer 5 of the mouse auditory cortex during optogenetic stimulation of specific classes of presynaptic neurons. Our results show that synaptic zinc potentiates AMPAR function in a synapse-specific manner. Specifically, in IT-PT synapses we observed unidirectional potentiation of AMPA receptors by zinc, while in IT-IT synapses we observed potentiation which could be enhanced or suppressed.

Additionally, ZnT3 and ZnT3-dependent synaptically released zinc may also play a role in the specific functional properties and structure of dendritic spines. How ZnT3 and ZnT3-dependent zinc may contribute to spine morphology and function presents a gap in our understanding of the range of zinc functions. To understand how zinc signaling contributes to the function of synapses, we performed whole-cell patch clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) from layer 5 PT-type corticocollicular neurons of wild type and ZnT3 knockout mice. Our results show that the constitutive loss of ZnT3 and ZnT3-dependent synaptically released zinc reduces mEPSC amplitudes in an age-dependent manner. We also utilized functional calcium imaging in this same population of neurons. These results showed that not all dendritic spine synapses are sensitive to zinc during activity.

This dissertation focuses on the cell-type specific effects of ZnT3-dependent synaptically released zinc on excitatory neurons in circuits of the mouse auditory cortex, and how ZnT3 and ZnT3-dependent synaptically released zinc function to determine the structural and functional properties of individual synapses. Our results provide insight into the contribution of zinc signaling to the functional specificity of cortical circuits and synaptic structure and function, as well as highlight the importance of further research to elucidate the wide range of signaling functions zinc may have across cell types and brain regions.

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