Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation

The N‐methyl‐d‐aspartate receptor plays a critical role in the formation and maintenance of synapses during brain development. In the rodent, changes in subunit expression and assembly of the heteromeric receptor complex accompany these maturational processes. However, little is known about N‐methyl‐d‐aspartate receptor subunit expression during human brain development. We used in situ hybridization to examine the distribution and relative abundance of NR1, NR2A and NR2B subunit messenger ribonucleic acids in the hippocampal formation and adjacent cortex of 34 human subjects at five stages of life (neonate, infant, adolescent, young adult and adult). At all ages, the three messenger ribonucleic acids were expressed in all subfields, predominantly by pyramidal neurons, granule cells and polymorphic hilar cells. However, their abundance varied across ontogeny. Levels of NR1 messenger ribonucleic acid in CA4, CA3 and CA2 subfields were significantly lower in the neonate than all other age groups. In the dentate gyrus, subiculum and parahippocampal gyrus, NR2B messenger ribonucleic acid levels were higher in the neonate than in older age groups. NR2A messenger ribonucleic acid levels remained constant, leading to an age‐related increase in NR2A/2B transcript ratio. We conclude that N‐methyl‐d‐aspartate receptor subunit messenger ribonucleic acids are differentially expressed during postnatal development of the human hippocampus, with a pattern similar but not identical to that seen in the rodent. Changes in subunit composition may thus contribute to maturational differences in human hippocampal N‐methyl‐d‐aspartate receptor function, and to their role in the pathophysiology of schizophrenia and other neurodevelopmental disorders.

[1]  Mark Farrant,et al.  NMDA receptor subunits: diversity, development and disease , 2001, Current Opinion in Neurobiology.

[2]  Paul J. Harrison,et al.  Glutamate Receptors and Transporters in the Hippocampus in Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[3]  C. Ikonomidou,et al.  Neuronal death enhanced by N-methyl-D-aspartate antagonists. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Suwaki,et al.  Identification of a novel variant of the human NR2B gene promoter region and its possible association with schizophrenia , 2002, Molecular Psychiatry.

[5]  J. Coyle,et al.  Glutamatergic mechanisms in schizophrenia. , 2003, Annual review of pharmacology and toxicology.

[6]  G. Collingridge,et al.  Excitatory amino acid receptors in the vertebrate central nervous system. , 1989, Pharmacological reviews.

[7]  Z. Fu,et al.  Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. , 2002, Molecular pharmacology.

[8]  P. Slater,et al.  Postnatal changes in N‐methyl‐D‐aspartate receptor binding and stimulation by glutamate and glycine of [3H]‐MK‐801 binding in human temporal cortex , 1993, British journal of pharmacology.

[9]  E. Aizenman,et al.  Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[10]  A. Represa,et al.  Transient increase of NMDA-binding sites in human hippocampus during development , 1989, Neuroscience Letters.

[11]  R. Gainetdinov,et al.  Genetic animal models: focus on schizophrenia , 2001, Trends in Neurosciences.

[12]  J. Hell,et al.  A Developmental Change in NMDA Receptor-Associated Proteins at Hippocampal Synapses , 2000, The Journal of Neuroscience.

[13]  W. Slikker,et al.  Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  E. Perry,et al.  Glutamate receptor binding in the human hippocampus and adjacent cortex during development and aging , 1996, Neurobiology of Aging.

[15]  H. Bading,et al.  Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways , 2002, Nature Neuroscience.

[16]  M. Constantine-Paton,et al.  The role of neural activity in synaptic development and its implications for adult brain function. , 1999, Advances in neurology.

[17]  G. Westbrook,et al.  The Incorporation of NMDA Receptors with a Distinct Subunit Composition at Nascent Hippocampal Synapses In Vitro , 1999, The Journal of Neuroscience.

[18]  J. Deakin,et al.  Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses , 2001, Neuroreport.

[19]  M. Dichter,et al.  Pharmacological Characterization of Heterodimeric NMDA Receptors Composed of NR 1a and 2B Subunits: Differences with Receptors Formed from NR 1a and 2A , 1995, Journal of neurochemistry.

[20]  Henry R. Bourne,et al.  Molecular machines integrate coincident synaptic signals , 1993, Cell.

[21]  S. Nakanishi,et al.  Molecular cloning and characterization of the rat NMDA receptor , 1991, Nature.

[22]  L. Mrzljak,et al.  Postnatal development of mossy cells in the human dentate gyrus: A light microscopic Golgi study , 1992, Hippocampus.

[23]  R. Malenka,et al.  An ER retention signal explains differences in surface expression of NMDA and AMPA receptor subunits , 2001, Neuropharmacology.

[24]  J. Xuereb,et al.  The messenger RNAs for the N-methyl- d-aspartate receptor subunits show region-specific expression of different subunit composition in the human brain , 1996, Neuroscience.

[25]  S. Adams,et al.  Human N-methyl-D-aspartate receptor modulatory subunit hNR2A: cloning and sequencing of the cDNA and primary structure of the protein. , 1994, Biochimica et biophysica acta.

[26]  I. Fried,et al.  Hippocampal N‐methyl‐D‐aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients , 1999, Annals of neurology.

[27]  M. Webster,et al.  Alterations in trkB mRNA in the human prefrontal cortex throughout the lifespan , 2002, The European journal of neuroscience.

[28]  K Naujoks,et al.  Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. , 1997, Brain research. Molecular brain research.

[29]  J. Meador-Woodruff,et al.  Ontogeny of ionotropic glutamate receptor expression in human fetal brain. , 2001, Brain research. Developmental brain research.

[30]  J. Deakin,et al.  NR2B-containing NMDA receptors are up-regulated in temporal cortex in schizophrenia. , 1999, Neuroreport.

[31]  A. Faden,et al.  Traumatic brain injury: developmental differences in glutamate receptor response and the impact on treatment. , 2001, Mental retardation and developmental disabilities research reviews.

[32]  J. Trojanowski,et al.  Human fetal hippocampal development: II. The neuronal cytoskeleton , 1996, The Journal of comparative neurology.

[33]  K. Williams,et al.  Expression of mRNAs Encoding Subunits of the NMDA Receptor in Developing Rat Brain , 1995, Journal of neurochemistry.

[34]  C. Portera-Cailliau,et al.  N‐Methyl‐d‐Aspartate Receptor Proteins NR2A and NR2B Are Differentially Distributed in the Developing Rat Central Nervous System as Revealed by Subunit‐Specific Antibodies , 1996, Journal of neurochemistry.

[35]  Paul J. Harrison,et al.  The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins , 1995, Neuroscience Letters.

[36]  R. V. Omkumar,et al.  Sequence determinants on the NR2A and NR2B subunits of NMDA receptor responsible for specificity of phosphorylation by CaMKII. , 2002, Biochimica et biophysica acta.

[37]  B. Sakmann,et al.  Developmental and regional expression in the rat brain and functional properties of four NMDA receptors , 1994, Neuron.

[38]  Joe Z Tsien,et al.  Linking Hebb’s coincidence-detection to memory formation , 2000, Current Opinion in Neurobiology.

[39]  N. Herschkowitz.  Neurological bases of behavioral development in infancy , 2000, Brain and Development.

[40]  M. Yuzaki,et al.  Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability. , 2002, Brain research. Molecular brain research.

[41]  M. Delivoria-Papadopoulos,et al.  NMDA receptor and neonatal hypoxic brain injury. , 2001, Mental retardation and developmental disabilities research reviews.

[42]  K. Williams,et al.  Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro , 1993, Neuron.

[43]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[44]  P. Seeburg,et al.  Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  S. Nakanishi,et al.  Molecular cloning and chromosomal localization of the key subunit of the human N-methyl-D-aspartate receptor. , 1993, The Journal of biological chemistry.

[46]  S. Adams,et al.  Human receptor modulatory subunit hNR3: cloning and sequencing of the cDNA and primary structure of the protein , 1995 .

[47]  D. Weinberger,et al.  From neuropathology to neurodevelopment , 1995, The Lancet.

[48]  M. Baybis,et al.  Differential Expression of GABA and Glutamate‐receptor Subunits and Enzymes Involved in GABA Metabolism between Electrophysiologically Identified Hippocampal CA1 Pyramidal Cells and Interneurons , 2003, Epilepsia.

[49]  Roberto Malinow,et al.  Subunit-Specific NMDA Receptor Trafficking to Synapses , 2002, Neuron.

[50]  Xiao-yan Zhang,et al.  Effect of developmental lead exposure on the expression of specific NMDA receptor subunit mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. , 2002, Neurotoxicology and teratology.

[51]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[52]  T. Guilarte,et al.  Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure , 1998, Brain Research.

[53]  J. Meador-Woodruff,et al.  Ontogeny of ionotropic glutamate receptor subunit expression in the rat hippocampus. , 2002, Brain research. Developmental brain research.

[54]  Y. Jan,et al.  Changing subunit composition of heteromeric NMDA receptors during development of rat cortex , 1994, Nature.

[55]  E. Benedikz,et al.  Cloning and expression of the human N-methyl-d-aspartate receptor subunit NR3A , 2002, Neuroscience Letters.

[56]  Masahiko Watanabe,et al.  Impairment of Suckling Response, Trigeminal Neuronal Pattern Formation, and Hippocampal LTD in NMDA Receptor ε2 Subunit Mutant Mice , 1996, Neuron.

[57]  R. Petralia,et al.  Trafficking of NMDA receptors. , 2003, Annual review of pharmacology and toxicology.

[58]  A. Wenzel,et al.  NMDA Receptor Heterogeneity During Postnatal Development of the Rat Brain: Differential Expression of the NR2A, NR2B, and NR2C Subunit Proteins , 1997, Journal of neurochemistry.

[59]  David A Lewis,et al.  Schizophrenia as a disorder of neurodevelopment. , 2002, Annual review of neuroscience.

[60]  H. Monyer,et al.  NR2A Subunit Expression Shortens NMDA Receptor Synaptic Currents in Developing Neocortex , 1997, The Journal of Neuroscience.

[61]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[62]  J. Penney,et al.  Expression of N‐Methyl‐D‐Aspartate receptor subunit mRNAs in the human brain: Hippocampus and cortex , 1998, The Journal of comparative neurology.

[63]  Paul J. Harrison,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Genes for Schizophrenia? Recent Findings and Their Pathophysiological Implications , 2022 .

[64]  L. Raymond,et al.  Subtype-Dependence of NMDA Receptor Channel Open Probability , 1999, The Journal of Neuroscience.

[65]  Differential NR2A and NR2B expression between trigeminal neurons during early postnatal development , 2002, Synapse.

[66]  J. Eberwine,et al.  Corticosteroid Regulation of Ion Channel Conductances and mRNA Levels in Individual Hippocampal CA1 Neurons , 1998, The Journal of Neuroscience.

[67]  V. Rampersad,et al.  Cloning and sequence analysis of cDNAs encoding human hippocampus N-methyl-D-aspartate receptor subunits: evidence for alternative RNA splicing. , 1993, Gene.

[68]  David G. Amaral,et al.  21 – Hippocampal Formation , 1990 .

[69]  R. Conley,et al.  Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. , 2000, The American journal of psychiatry.

[70]  J. Trojanowski,et al.  Human fetal hippocampal development: I. Cytoarchitecture, myeloarchitecture, and neuronal morphologic features , 1996, The Journal of comparative neurology.

[71]  E. B. Roberts,et al.  Enhanced NR2A subunit expression and decreased NMDA receptor decay time at the onset of ocular dominance plasticity in the ferret. , 1999, Journal of neurophysiology.

[72]  M. Bear,et al.  Visual Experience and Deprivation Bidirectionally Modify the Composition and Function of NMDA Receptors in Visual Cortex , 2001, Neuron.

[73]  Bert Sakmann,et al.  Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes , 1992, Science.

[74]  D. Feldmeyer,et al.  Functional Correlation of NMDA Receptor ε Subunits Expression with the Properties of Single-Channel and Synaptic Currents in the Developing Cerebellum , 1996, The Journal of Neuroscience.