FUNCTIONAL PLASTICITY OF HIPPOCAMPAL GLUTAMATERGIC SYNAPSES IN DEVELOPMENT AND DISEASE

The establishment and maintenance of synaptic connections are critical for the normal function of the central nervous system. The function of mature neural circuits depends critically on the appropriate apposition of preand postsynaptic specializations and on the spatial organization of synapses along axon arbors and postsynaptic dendrites. In neurological disease, the integrity of these processes may be compromised or lost, resulting in profound cognitive and behavioral deficits. In my thesis work, I have investigated the spatial distribution of functional properties of presynaptic terminals along axon arbor, and the determinants of these properties across different spatial scales. My results suggest that, for a single axonal arbor, presynaptic strength over short distances is determined by variations in total vesicle pool size, whereas over longer distances presynaptic strength is determined by the spatial modulation of release fraction. Thus the mechanisms that determine synaptic strength differ depending on spatial scale. I have also examined the structural and functional consequences of loss of postsynaptic components, NMDA and AMPA type glutamate receptors, that occur in two forms of human autoimmune encephalitis in which these proteins are specifically targeted, and that result in dramatic deficits in cognition and behavior. My results suggest that patient antibodies against these two types of glutamate receptors selectively result in the internalization of receptor from the neuron surface, decreasing synaptic localization, currents and thus influencing synaptic function. My work extends our understanding of the repertoire of preand postsynaptic mechanisms that are required to establish and maintain functional neural circuits during development and in diseases that compromise nervous system function. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Biology First Advisor Rita J. Balice-Gordon Second Advisor Thomas D. Parsons