Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Tore Eid

Subject Area(s)

Neurosciences, Medicine

Abstract

Mesial temporal lobe epilepsy (MTLE) development in humans is frequently heralded by an initial brain insult, followed by a latent period, and culminating in spontaneous recurrent seizures. Patients with this disorder are deficient in the glutamate metabolizing enzyme glutamine synthetase (GS) in the epileptogenic hippocampal formation and also have chronically increased levels of extracellular glutamate in this region. Inhibition of GS by infusion of the irreversible enzyme inhibitor, methionine sulfoximine (MSO), unilaterally into the hippocampus of rats serves as a reasonable model for MTLE. We hypothesized that inhibition of GS by MSO would directly result in an elevation of extracellular glutamate, and that this elevation would occur early in the latent period prior to seizure onset. Microdialysis was used to sample hippocampal extracellular fluid, and mass spectrometry was utilized to analyze neurotransmitter concentrations.

Microdialysis experiments analyzing baseline neurotransmitter concentrations in acute (post-surgery day 7) and chronic (post-surgery day 21) MSO animals demonstrated a trend toward increasing glutamate concentrations as time progressed, while glutamine appeared to decrease with time. This observation was only made on the contralateral side to the MSO injection site. Infusion of potassium demonstrated a diminished threshold of excitability compared to control, and demonstrated a higher proportion of severe seizures in acute (65%) compared to chronic animals (17%), although sample size was very small in all groups and will require further investigation.

This is the first report of extracellular glutamate assessments in the hippocampus by microdialysis in the intracerebral MSO model of MTLE. Given the small sample size, no conclusions can be made but results are encouraging and future studies should be conducted to achieve statistical significance.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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