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 R1 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 R1–1 and N -methyl- d -aspartate R1–3 but not N -methyl- d -aspartate R1–2; 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 1 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.