Date of Award

December 2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Advisor(s)

Sandra J. Hewett

Keywords

Excitatory/inhibitory balance, System xc-, xCT

Subject Categories

Life Sciences

Abstract

System xc- (Sxc-) is a cellular antiporter that links the import of L-cystine with the export of L-glutamate. In the central nervous system (CNS), this export contributes to the ambient glutamate levels found in the synaptic cleft. To wit, a 50% reduction in extracellular glutamate has been demonstrated in animals null for the substrate-specific light chain, xCT. Moreover, in most tissues, including the CNS, cystine import through Sxc- is necessary for the synthesis and maintenance of glutathione (GSH) levels. Given that either a reduction in ambient glutamate levels and/or a redox imbalance involving GSH have been reported to affect synaptic strength and intrinsic neuronal excitability, the main focus of this dissertation was to elucidate whether Sxc- signaling contributes to brain excitatory/inhibitory (E/I) balance in vivo. Using chemoconvulsants to uncover excitability changes in SLC7A11sut/sut mice — mice that are null for Sxc- because of a spontaneous mutation in exon 12 of SLC7A11 — we uncovered a sex-independent alteration in neuronal excitability. Specifically, we found that both female and male SLC7A11sut/sut mice had lower convulsive seizure thresholds than their wild-type (SLC7A11+/+) littermates after acute challenge with two pharmacologically distinct chemoconvulsants: the glutamate receptor agonist, kainic acid (KA), or the GABAA receptor antagonist, pentylenetetrazole (PTZ). Paradoxically, after repeated repeated/chronic administration of the same chemoconvulsants, SLC7A11sut/sut mice exhibit signs of hypo-excitability, a response polar opposite to that which occurs in SLC7A11+/+ littermate controls. Whether the aberrant neuronal excitability in SLC7A11sut/sut mice occurred in association with alterations in brain morphology – at the gross, cellular, and sub-cellular level – or with alterations in redox balance or plasma membrane protein expression levels, was also investigated. Overall, our data demonstrate that neuronal excitability in SLC7A11sut/sut mice provoked by chemoconvulsant challenge deviates from that of SLC7A11+/+ littermates in a complex manner that differs in sign depending on the chemoconvulsant dosing paradigm employed. Moreover, mutations in Sxc- trigger sex-dependent changes in redox status, brain morphology, and plasma membrane protein expression, any or all of which could contribute to the observed E/I imbalance in SLC7A11sut/sut mice.

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