All ETDs from UAB

Advisory Committee Chair

Jacques I Wadiche

Advisory Committee Members

Lynn E Dobrunz

Linda Overstreet-Wadiche

Erik D Roberson

Harald Sontheimer

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Glutamate is the most prominent fast excitatory neurotransmitter released at mammalian central synapses, where point-to-point activation of receptors in postsynaptic densities is accepted to be the primary pathway for information flow through neural circuits. More controversial are the activities of synaptically-released glutamate outside the synaptic cleft of origin, as "spillover" glutamate may signal through neighboring synapses or through extrasynaptic receptors. The role of such extrasynaptic signaling in physiological neuronal communication is unproven and its inappropriate occurrence has been proposed to underlie a range of neurodegenerative conditions. Elucidation of spillover signaling mechanisms thus benefits our understanding of the brain in both intact and diseased states. This thesis examines both the mechanisms and consequences of pure spillover transmission as it occurs in the cerebellum when glutamate escapes climbing fiber-to-Purkinje cell synapses to activate local molecular layer interneurons in the absence of anatomically-defined synapses. The phenomenon of CF-to-MLI pure spillover transmission offers a rare opportunity to study the physiological activation of glutamate receptors by subsaturating concentrations of transmitter outside the controlled synaptic environment. In addition, it represents a virtually unexplored avenue for information transfer within the cerebellar cortex, a model system in which information transfer has been studied for over a century. I show that spillover from a single CF entrains the activity of multiple local MLIs, thereby rearranging ongoing GABAergic activity onto a functionally-defined microcircuit of neighboring Purkinje cells. Spillover-induced feed-forward inhibition leads to synchronous activity of interconnected interneurons, necessitating computation of ongoing excitation and inhibition by each participating MLI. In addition, I explore the synaptic mechanisms that underlie excitation of MLIs by CF spillover glutamate. I show that while spillover seems to contact a privileged group of extrasynaptic GluA2-containing AMPARs, there is no evidence for the maintenance of such a population on MLI membranes. Rather, low spillover concentrations and high synaptic concentrations of glutamate may contact equivalent receptor populations but recruit qualitatively different responses. The results of this dissertation expand the knowledge of functional cerebellar circuitry, AMPA receptor recruitment by glutamate, and of the fundamental capacity for information flow between neurons in the central nervous system.

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