Neurotransmitter Receptor Plasticity and Its Functional Consequences in Relation to Alzheimer's Disease

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, des