Date of Award

Summer 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Rita J. Balice-Gordon, Ph.D.

Abstract

ABSTRACT

MECHANISMS OF SYNAPSE FORMATION AND MAINTENANCE: INSIGHTS FROM THE DEVELOPING AND DISEASED NERVOUS SYSTEM

Ethan G. Hughes

Rita J. Balice-Gordon, Ph.D.

The formation and maintenance of synapses is essential for the central nervous system (CNS) to function. In the developing nervous system, the assembly of synaptic circuits is a complex and dynamic process, requiring the coordinated exchange of signals between pre- and postsynaptic neurons and surrounding glia. The maintenance and modulation of synaptic connections is required for normal CNS function and ongoing plasticity. The structural and functional integrity of synaptic connections is often modified or lost in the diseased nervous system, resulting in profound cognitive and behavioral deficits. While some aspects of the mechanisms underlying the formation, maintenance and plasticity of CNS synapses in the developing and diseased nervous system have been elucidated, many more remain to be understood.

In my thesis work, I have examined the role of astrocytes in the development of GABAergic hippocampal synapses in in vitro models. I have also examined the maintenance of glutamatergic synapses in in vitro and in vivo models of anti-NMDAR encephalitis, an immune-mediated disorder of memory and behavior. First, I demonstrate that secreted factors released from astrocytes specifically increase GABAergic axon length, branching, and synaptogenesis, that these effects are not mediated by several well-known candidates, and that the secreted factors from astrocytes are proteins. Second, I examined the identity of the proteins released from astrocytes that affect GABAergic neurons using size fractionation, mass spectroscopy, and computational analyses. Third, I examined the cellular and synaptic mechanisms underlying anti-NMDAR encephalitis and investigated the effects of autoantibodies from patients with this disorder on the maintenance and function of CNS excitatory synapses. Together, my work extends our understanding of how neuron-glial communication modulates the formation of synapses in the developing brain, and how the disruption of synapse maintenance may underlie cognitive deficits in the diseased nervous system.

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