All ETDs from UAB

Advisory Committee Chair

Jacques I Wadiche

Advisory Committee Members

Candace Floyd

John J Hablitz

Gwendalyn King

Linda Overstreet-Wadiche

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In recent years, a form of extrasynaptic signaling through fast neurotransmitters, termed spillover, has been shown in multiple brain regions. This discovery suggests that spillover is more ubiquitous than previously thought. The circuitry within the cerebellar cortex has been well mapped. However, glutamate from cerebellar climbing fibers (CF) has been shown to spill over to nearby interneurons and alter their tonic activity. Cerebellar Golgi cells are spontaneously active interneurons at the input stage to the cerebellar cortex re-sponsible for regulating influx of cortical information. Previous research has shown an in vivo connection between CFs and Golgi cells (GoC), with CF activation dampening GoC tonic activity. Anatomical investigations have been unable to find evidence for synapses between CFs and GoCs. One possibility is that there is a multisynaptic connection pro-ducing the dampening of GoC firing. Another possibility is that CFs directly activate post-synaptic receptors on GoCs through spillover transmission. This dampening of GoC activity may be important for cerebellar information processing and motor learning. The following studies address the mode of transmission between CFs and GoCs, showing that CFs signal through spillover transmission. This results in monophasic excitation or biphasic excitation and inhibition mediated by post-synaptic mGluR2 activation. Addi-tionally, we provide evidence showing spillover transmission showing that it is spatially restricted, activates a distinct subset of glutamate receptors, and GoCs with CF input may share similar space in the cortex with simultaneously recorded PCs, used to infer CF loca-tion. These studies highlight the potential limits of CF spillover and the consequences of spillover signaling in the brain.

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