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Wiring Of Presynaptic Inhibitory Circuitry In The Mouse Spinal Cord

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Abstract

Proper neural circuit development, organization, and function are essential to produce correctly executed behaviors. Neural circuits in the spinal cord process sensory information, and coordinate movement. One essential circuit in the spinal cord that has been well studied is the sensory-motor reflex circuit. This circuit is subject to interneuron modulation, specifically by inhibitory GABAergic interneurons, termed GABApre neurons. GABApre neurons exert presynaptic inhibition by forming synaptic boutons on sensory afferent terminals and thereby controlling sensory signaling onto motor neurons. Previous work on GABApre neurons has identified that they express specific synaptic markers, possess stringent specificity with their sensory neuron synaptic partner, and play a role in mediating smooth movement. Deficits in presynaptic inhibition have been observed in human diseases, such as dystonia and Parkinson’s disease. GABApre neurons exert presynaptic inhibition but their molecular profile and contribution to motor disease is not well known. In this dissertation, I examine the molecular profile of GABApre neurons, and their potential link to the motor disease, dystonia. I show that the kelch-like family member 14 (Klhl14) identified from a screen for genes enriched in the intermediate spinal cord, is expressed in GABApre neurons. Klhl14 directly binds the torsin family 1, member A (Tor1a) dystonia protein, which is co-expressed in GABApre neurons. Further, I show that when Tor1a is mutated in such a way that disrupts its binding with Klhl14, there is a reduction in the number of properly formed GABApre boutons, providing a link between GABApre circuitry and motor disease.

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2016

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dystonia; mouse; neuroscience; presynaptic inhibition; spinal cord; synapse

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Neuroscience

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Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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