Expression of the N-Methyl-D-Aspartate Receptor Subunit R1 in the Developing Human Hippocampus

Abstract

It has been suggested that the N-methyl-D-aspartate (NMDA) receptor family plays a key role in synaptic plasticity and synaptogenesis that is essential for memory, learning, differentiation, and development. Although gene expression of these receptors has been analyzed in the experimental animal brain and in some diseases of the adult or elderly human brain, it has not been studied in the developing human brain. Using in situ hybridization, we investigated the expression of the NMDAR1 gene in the hippocampi of 16 human neonates who were between 22 and 40 weeks of gestation and had no evidence of critical episodes of brain insult at autopsy. Signals for NMDAR1 were detected ubiquitously at all developmental stages. Dense hybridization signals were uniformly detected in the granular cells of the dentate gyrus in all specimens. Stronger signals were observed in the larger-type pyramidal cells in the CA2 and CA3 regions compared with the pattern seen in the CA1 region in the smaller-type pyramidal cells. These results suggest that the NMDAR1 gene is expressed at 22 weeks and possibly occurs earlier in neuronal cell bodies of the dentate gyrus and all CA fields of Ammon's horn and that the NMDAR plays an important role in constructing neuronal networks in developing human brains. (J Child Neurol 2006;21:236—239; DOI 10.2310/7010.2006.00060).

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References

Monaghan DT , Bridges RJ , Cotman CW : The excitatory amino acid receptors: Their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol 1989;29:365—402.

Collingridge GL , Lester RA : Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 1989 ;40:143—210.

Watanabe M. , Inoue Y. , Sakimura K. , Mishina M. : Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport 1992;3:1138—1140.

Akazawa C. , Shigemoto R. , Bessho Y. , et al: Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J Comp Neurol 1994;347:150—160.

Meoni P. , Bunnemann BH , Trist DG , Bowery NG : N-terminal splice variants of the NMDAR1 glutamate receptor subunit: Differential expression in human and monkey brain. Neurosci Lett 1998;249:45—48.

Herlenius E. , Lagercrantz H. : Neurotransmitters and neruomodulators during early human development. Early Hum Dev 2001 ;65:21—37.

Laurie DJ , Seeburg PH : Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J Neurosci 1994;14:3180—3194.

Ozawa S. , Kamiya H. , Tsuzuki K. : Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 1998;54:581—618.

Johnston MV , Jean OH , Pevsner J. , et al: Neurobiology of Rett syndrome: A genetic disorder of synapse development. Brain Dev 2001;23(Suppl 1):S206—S213.

10.

Puka-Sundvall M. , Hallin U. , Zhu C. , et al: NMDA blockade attenuates caspase-3 activation and DNA fragmentation after neonatal hypoxia-ischemia. Neuroreport 2000;11:2833—2836.

11.

Fried I. , Assirati JA , Ojemann GA , et al: Hippocampal N-methylD-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients. Ann Neurol 1999;46:343—358.

12.

Blumcke I. , Beck H. , Scheffler B. , et al: Altered distribution of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit GluR2(4) and the N-methyl-D-aspartate receptor subunit NMDAR1 in the hippocampus of patients with temporal lobe epilepsy . Acta Neuropathol (Berl) 1996;92:576—587.

13.

Law AJ , Deakin JF : Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 2001;12:2971—2974.

14.

Meador-Woodruff JH , Healy DJ : Glutamate receptor expression in schizophrenic brain. Brain Res Brain Res Rev 2000;31:288—294.

15.

Ikonomovic MD , Mizukami K. , Warde D. , et al: Distribution of glutamate receptor subunit NMDAR1 in the hippocampus of normal elderly and patients with Alzheimer's disease. Exp Neurol 1999;160:194—204.

16.

Böckers TM , Zimmer M. , Müller A. , et al: Expression of the NMDA R1 receptor in selected human brain regions . Neuroreport 1994;5:965—969.

17.

Moriyoshi K. , Masu M. , Ishii T. , et al: Molecular cloning and characterization of the rat NMDA receptor. Nature 1991;354:31—37.

18.

Kutsuwada T. , Kashiwabuchi N. , Mori H. , et al: Molecular diversity of the NMDA receptor channel. Nature 1992;358:36—41.

19.

Meguro H. , Mori H. , Araki K. , et al: Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature 1992;357:70—74.

20.

Yamazaki M. , Mori H. , Araki K. , et al: Cloning, expression and modulation of a mouse NMDA receptor subunit. FEBS Lett 1992;300:39—45.

21.

Laube B. , Kuhse J. , Betz H. : Evidence for a tetrameric structure of recombinant NMDA receptors. J Neurosci 1998;18:2954—2961.

22.

Collingridge GL , Bliss TV : Memories of NMDA receptors and LTP. Trends Neurosci 1995;18:54—56.

23.

Bliss TV , Collingridge GL : A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 1993;361:31—39.

24.

Choi DW : Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1:623—634.

25.

Olney JW : Excitotoxic amino acids and neuropsychiatric disorders. Annu Rev Pharmacol Toxicol 1990;30:47—71.