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Title: Homocysteine alters hippocampal signalling in vitro and ex vitro
Author: Christie, Louisa A.
ISNI:       0000 0001 3549 3755
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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The focus of this thesis was to investigate the non-essential, sulphur-containing amino acid homocysteine (HCY); elevations in plasma HCY have been associated with several pathological states in the elderly; age-associated reductions in vitamins, essential for the metabolism of HCY, are common and this situation is exacerbated during Alzheimer’s disease (AD).  Primary culture preparations of hippocampal tissue were utilised to investigate intracellular signalling and Ca2+ homeostasis, which were monitored using the Ca2+ fluorescent dye Fluo-4.  In the present study hippocampal slices were prepared from adult rats.  In Fluo 4 Ca2+ imaging studies, HCY (10, 100 µM and 1 mM) added acutely, caused rises in intracellular Ca2+ and decreased NMDA-induced Ca2+ responses.  Pharmacological investigations confirmed that the primary Ca2+ influx following addition of HCY (1 mM) was not mediated via NMDA, group I mGluRs, glycine or GABA receptors, voltage-gated Ca2+ channels (VGCCs) or intracellular stores (ER).  Results with specific antagonists indicate that HCY may have a partial interaction with NMDA receptors and intracellular stores; additionally, experiments revealed that HCY may antagonise the glycine co-agonist binding site on the NMDA receptor and may depend of HCY dose or competition with other glycine site modulators.  Acute application of HCY in slices (10 µM - 1 mM) in vitro caused a dose-response effect with lower concentrations impairing and higher doses enhancing LTP.  With different systemic routes and longer durations (with two concentrations: 20 and 200 mg/kg) basic transmission and LTP were altered in a bi-directional as well as concentration- and time-dependent manner, suggestive of diverse and complex targets for HCY.  Overall, the observed HCY-induced functional alterations amid lack of severe toxicity in vitro and ex vivo in healthy cells suggest a possible contribution in aged or diseased tissues, making this an extremely important consideration for future research as well as for dietary considerations in the elderly.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available