title: The messenger RNAs for the N-methyl-D-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain.
abstract: The expression of the messenger RNAs encoding N-methyl-D-aspartate receptor subunits in neurologically normal post-mortem human brain was studied by in situ hybridization. In the caudate, putamen and nucleus accumbens strong hybridization signals were observed for N-methyl-D-aspartate R1-1 messenger RNA but much weaker signals for N-methyl-D-aspartate R1-3 and N-methyl-D-aspartate R1-4, N-Methyl-D-aspartate R1-2 was not detectable. N-methyl-D-aspartate R2B was the only N-methyl-D-aspartate R2 subunit detected in these nuclei. In the hippocampus the messenger RNAs for both N-methyl-D-aspartate R1-1 and N-methyl-D-aspartate R1-4 were strongly expressed in the dentate gyrus, CA3-CA1 pyramidal cells, subiculum, entorhinal cortex and perirhinal cortex. Much lower expression was seen for N-methyl-D-aspartate R1-2 and N-methyl-D-aspartate R1-3. The messenger RNAs for both N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2B, but not N-methyl-D-aspartate R2C, subunits were expressed in the hippocampus. In the temporal cortex all N-methyl-D-aspartate RI isoforms were expressed (N-methyl-D-aspartate R1-1 and N-methyl-D-aspartate R1-4 being the most abundant) and N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2B but not N-methyl-D-aspartate R2C were also moderately expressed. In the brain stem N-methyl-D-aspartate R1-4 was strongly expressed in various nuclei including the locus coeruleus, nucleus centralis superior and deep pontine nuclei. Only weak expression was seen for N-methyl-D-aspartate RI-1 and N-methyl-D-aspartate R1-3 but not N-methyl-D-aspartate RI-2; of the N-methyl-D-aspartate R2 subunits only N-methyl-D-aspartate R2C was found to be expressed in these nuclei. In the cerebellum all the N-methyl-D-aspartate I isoforms were expressed (mostly N-methyl-D-aspartate R1-4) in the Purkinje layer which also expressed N-methyl-D-aspartate R2A and N-methyl-D-aspartate R2C. In the molecular layer cells were found expressing N-methyl-D-aspartate R1-4 and N-methyl-D-aspartate R2B and cells in the granule layer were found to express N-methyl-D-aspartate R1-1, N-methyl-D-aspartate R1-3 and N-methyl-D-aspartate R1-4 and N-methyl-D-aspartate R2C only. Preliminary studies indicated that the messenger RNA for the N-methyl-D-aspartate R2D subunit was not expressed in the above areas of brain. These results give the first demonstration of the distribution of N-methyl-D-aspartate receptor subunit messenger RNAs in the human brain. The region-specific expression of subunit combinations suggests a heterogeneity of N-methyl-D-aspartate receptors with diverse physiological/pathophysiological roles and provides a rationale for the development of discriminatory N-methyl-D-aspartate receptor antagonists to target selective neuronal populations.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
authors.forename: M
authors.initials: M
authors.lastname: Rigby
authors.forename: B
authors.initials: B
authors.lastname: Le Bourdellès
authors.forename: R P
authors.initials: RP
authors.lastname: Heavens
authors.forename: S
authors.initials: S
authors.lastname: Kelly
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Butler
authors.forename: R
authors.initials: R
authors.lastname: Hammans
authors.forename: R
authors.initials: R
authors.lastname: Hills
authors.forename: J H
authors.initials: JH
authors.lastname: Xuereb
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: P J
authors.initials: PJ
authors.lastname: Whiting
authors.forename: D J
authors.initials: DJ
authors.lastname: Sirinathsinghji
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography / Q000379:methods; D001479:Basal Ganglia / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D015345:Oligonucleotide Probes; D009928:Organ Specificity; D017966:Pyramidal Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000737:chemistry; D013462:Sulfur Radioisotopes; D013702:Temporal Lobe / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D013462:Sulfur Radioisotopes