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Title: Neurotransmitter receptor plasticity and its functional consequences in relation to Alzheimer's disease
Author: Chalmers, Derek T.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1989
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Neurotransmitter receptor sites have been examined in both human postmortem tissue and a lesioned polysynaptic pathway in rat brain using quantitative ligand binding autoradiography. Human Postmortem Studies The putative involvement of glutamatergic mechanisms in the pathophysiology of Alzheimer's disease (A. D. ) was investigated by determining the distribution and density of Na+ -dependent glutamate uptake sites and glutamate receptor subtypes; kainate, quisqualate and N-methyl-D-aspartate (NMDA), in adjacent sections of frontal, temporal and cerebellar cortex from six patients with A. D. and six age-matched controls. The number of senile plaques in each region was determined in adjacent sections to those used for receptor autoradiography. Binding of [3H]-D-aspartate to Na+-dependent uptake sites was reduced by approximately 40% throughout A. D. frontal cortex relative to controls, indicating a general loss of glutamatergic presynaptic terminals. [3H]-Kainate binding was significantly increased by approximately 70% in deep layers of A. D. frontal cortex compared to controls, but unaltered in superficial laminae. Scatchard analysis of this response indicated an increase in kainate receptor numbers with no change in receptor affinity. [3H]-Kainate binding and senile plaque numbers were positively correlated (r=0.914) in deep layers of A. D. frontal cortex, but unrelated in superficial laminae (r=0.089). There was a small reduction (25%) in NMDA-sensitive [3H]-glutamate binding only in superficial layers of A. D. frontal cortex relative to controls, although [3H]-glutamate binding in A. D. subjects was unrelated to senile plaque numbers in these cortical layers (r=0.104). Quisqualate receptors, as assessed by [3H]-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]-AMPA) binding were unaltered in A. D. frontal cortex compared to controls. There was no significant alteration in any glutamate binding sites in A. D. temporal cortex relative to control brains, despite the presence of senile plaques in comparable numbers to those found in A. D. frontal cortex. However, in the molecular layer of cerebellar cortex from A. D. subjects, there was a significant reduction (40%) in the number of [3H]-AMPA binding sites indicating a loss of quisqualate receptors in this region. [3H]-D-aspartate, [3H]-kainate and NMDA-sensitive [3H]-glutamate binding were unaltered in either the molecular or granule cell layers of A. D. cerebellar cortex. Within the cerebellum, senile plaques were found in very small numbers in only two A. D. brains. These results indicate anatomically-selective alterations in glutamatergic sites within the A. D. brain. The association of the kainate response in frontal cortex with the level of local neuropathology and the loss of quisqualate receptors in the cerebellum in the absence of gross neuropathological change suggests that the mechanisms of glutamatergic dysfunction in A. D. are heterogeneous with respect to anatomical locus. Rat Visual System Studies The rat visual system was employed as a model polysynaptic pathway in which to examine neurotransmitter receptor alterations under conditions of functional deficit. Within the visual system, glutamate is the major excitatory transmitter, although serotonin, noradrenaline, acetylcholine and GABA (y-aminobutyric acid) are also involved in visual processing. Unilateral orbital enucleation experiments were undertaken to examine: (1) the response of glutamate receptor subtypes under conditions of reduced glutamatergic input; (2) receptor regulation in separate but functionally related systems, by simultaneously quantifying specific serotonergic, noradrenergic, GABAergic and cholinergic receptors post-lesion; and (3) the relevance of alterations in neurotransmitter receptors to changes in local cerebral function, by combining the [14C]-2-deoxyglucose technique for the measurement of cerebral glucose use with in vitro receptor autoradiography. The results presented in this thesis highlight the applicability of quantitative receptor autoradiography in studies of receptor dynamics in both rat polysynaptic systems and human neurodegenerative disease. The novel alterations in glutamatergic sites in the A. D. brain uncovered by the present investigations provide new insight into the role of glutamatergic dysfunction in the pathophysiology of the disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available