Publication Date

2016-02-16

Availability

Embargoed

Embargo Period

2018-02-15

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2015-12-16

First Committee Member

Kenneth J. Muller

Second Committee Member

Jeffrey L. Goldberg

Third Committee Member

John N. Barrett

Fourth Committee Member

Laura Bianchi

Fifth Committee Member

Stephen D. Roper

Sixth Committee Member

Pantelis Tsoulfas

Abstract

How does a stem cell differentiating into a neuron acquire its electrical properties and integrate into functional neural circuits? During development, retinal ganglion cells (RGCs), for example, differentiate from retinal progenitor cells, become electrically active, make synapses, and display distinctive firing and synaptic properties. However, the regulation of such developmental processes is not well understood. With increasing interest in stem cell-derived therapy research, it is important to study the developmental state of neurons generated in vitro and investigate its contribution to implementing cell replacement therapies. Using the retina and retinal cells as representative of central nervous system (CNS) neurons, I have addressed some unanswered questions about neuronal development and the potential for cell replacement in the CNS. In this dissertation, I have shown evidence that physiologic maturation of GABA receptor responses in RGCs is regulated extrinsically. As a step towards evaluating the potential of cell replacement therapies in the CNS, I have also described a cell transplantation model in the retina. In this model, purified early postnatal RGCs were shown to survive, synaptically integrate into adult host retinas, and respond to light flashes, excited by light on or off or both, indicating that functionally immature neurons can integrate into neural circuits. This work is a step forward in understanding the regulation of physiological changes occurring during development, and their importance in achieving successful stem cell-to-neuron therapies in the future.

Keywords

Neuronal maturation, cell transplantation, retinal ganglion cells, glaucoma, GABA maturation, transplant integration

Available for download on Thursday, February 15, 2018

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