AMPA KAINATE RECEPTOR GENE-EXPRESSION IN NORMAL AND ALZHEIMERS-DISEASE HIPPOCAMPUS/

Alzheimer's disease is a progressive dementia characterized by pronoun ced degeneration of certain populations of neurons in the hippocampus and cerebral cortex of the brain. One theory is that glutamate recepto r-mediated toxicity plays a role in cell loss associated with Alzheime r's disease. We used in situ hybridization to examine GluR1, GluR2, an d GluR3 messengerRNAs (encoding alpha-amino-3-hydroxy-5-methyl-4-isoxa zole propionic acid/kainate receptor subunits) in sections of autopsy samples of Alzheimer's disease brains and age-, sex-, and post-mortem delay-matched brains from non-demented (control) subjects. GluR1 and G luR2 exhibited a heterogeneous distribution in control brain. GluR1 wa s expressed in granule cells of the dentate gyrus, in pyramidal cells of the CA1 and CA3 hippocampal subfields and in neurons of the subicul um and entorhinal cortex. GluR2 mRNA was at high density in the dentat e gyrus and in CA3, but was at low density in CA1, subiculum, and ento rhinal cortex. GluR3 hybridization was at very low levels but selectiv ely localized to the dentate gyrus and CA3. In cerebellum GluR1 was fo und in granule and Purkinje cell layers. In sections from Alzheimer's disease brain, a high degree of intersubject variability was observed: some samples showed markedly reduced GluR1 mRNA levels in dentate gyr us, CA1 and CA3 relative to controls; others showed no changes. Micros copic observation of emulsion-dipped sections revealed that the reduct ion of GluR1 seen in the dentate gyrus and CA3 of some Alzheimer's dis ease subjects was not due to cell loss. Due to generally low hybridiza tion signals obtained for GluR2 and GluR3, only GluR1 could be reliabl y quantitated. When hybridization densities were correlated with a num ber of pre- and post-mortem variables, a significant negative correlat ion (r = -0.68, P = < 0.01) was found between the storage duration of brain samples and GluR1 messengerRNA levels in dentate gyrus. Our resu lts show that GluR1 messengerRNA is not changed in Alzheimer's disease hippocampus; relative to storage interval-matched control hippocampus ; all of the differences in mean expression levels between Alzheimer a nd control brains could be ascribed to greater post-mortem storage tim e of tissue samples. The feasibility of studies of glutamate receptor messengerRNA levels in neurological diseases of humans is demonstrated , as is the importance of controlling for variations in handling of ti ssues.