Synaptophysin protein and mRNA expression in the human hippocampal formation from birth to old age

In the human neocortex, progressive synaptogenesis in early postnatal life is followed by a decline in synaptic density, then stability from adolescence until middle age. No comparable data are available in the hippocampus. In this study, the integral synaptic vesicle protein synaptophysin, measured immunoautoradiographically, was used as an index of synaptic terminal abundance in the hippocampal formation of 37 subjects from 5 weeks to 86 yr old, divided into 4 age groups (10 infants, 15 adolescents/young adults, 6 adults, and 6 elderly). In all hippocampal subfields, synaptophysin was lowest in infancy, but did not differ significantly between the older age groups, except in dentate gyrus (DG) where the rise was delayed until adulthood. A similar developmental profile was found in the rat hippocampus. We also measured synaptophysin mRNA in the human subjects and found no age‐related changes, except in parahippocampal gyrus wherein the mRNA declined from infancy to adolescence, and again in old age. The synaptophysin protein data demonstrate a significant presynaptic component to human postnatal hippocampal development. In so far as synaptophysin abundance reflects synaptic density, the findings support an increase in hippocampal and parahippocampal synapse formation during early childhood, but provide no evidence for adolescent synaptic pruning. The mRNA data indicate that the maturational increases in synaptophysin protein are either translational rather than transcriptional in origin, or else are secondary to mRNA increases in neurons, the cell bodies of which lie outside the hippocampal formation. Published 2006 Wiley‐Liss, Inc.

[1]  Paul J. Harrison,et al.  Schizophrenia: a genetic disorder of the synapse? , 2005, BMJ : British Medical Journal.

[2]  Fred H. Gage,et al.  Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat , 1991, Experimental Neurology.

[3]  Yevgenia Kozorovitskiy,et al.  Experience induces structural and biochemical changes in the adult primate brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[4]  P. Goldman-Rakic,et al.  Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness. , 1994, Progress in brain research.

[5]  Paul J. Harrison,et al.  Immunoautoradiographic evidence for a loss of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate-preferring non-N-methyl-D-aspartate glutamate receptors within the medial temporal lobe in schizophrenia , 1997, Biological Psychiatry.

[6]  Paul J. Harrison,et al.  Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia , 2001, Hippocampus.

[7]  Karyn M. Frick,et al.  Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice , 2003, Neurobiology of Aging.

[8]  P. Huttenlocher Synaptic density in human frontal cortex - developmental changes and effects of aging. , 1979, Brain research.

[9]  Y. Goda,et al.  Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Daly,et al.  Post-Transcriptional Regulation of Synaptic Vesicle Protein Expression and the Developmental Control of Synaptic Vesicle Formation , 1997, The Journal of Neuroscience.

[11]  G. Lynch,et al.  A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. , 1973, Brain research.

[12]  E. Ulupınar,et al.  Prenatal stress reduces interneuronal connectivity in the rat cerebellar granular layer. , 2005, Neurotoxicology and teratology.

[13]  P. Hof,et al.  Hemispheric asymmetry, modular variability and age-related changes in the human entorhinal cortex , 2005, Neuroscience.

[14]  Paul J. Harrison,et al.  Changes in NMDA Receptor Subunit mRNAs and Cyclophilin mRNA during Development of the Human Hippocampus , 2003, Annals of the New York Academy of Sciences.

[15]  Paul J. Harrison,et al.  Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography , 1995, Neuroscience.

[16]  P S Goldman-Rakic,et al.  Synaptogenesis in the prefrontal cortex of rhesus monkeys. , 1994, Cerebral cortex.

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

[18]  Nicholas Lange,et al.  Two-dimensional versus three-dimensional cell counting: a practical perspective , 2001, Trends in Neurosciences.

[19]  E. Masliah,et al.  Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease , 1989, Neuroscience Letters.

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

[21]  M. Colonnier,et al.  Postnatal changes in the number of neurons and synapses in the visual cortex (area 17) of the macaque monkey: A stereological analysis in normal and monocularly deprived animals , 1982, The Journal of comparative neurology.

[22]  W. Honer Pathology of presynaptic proteins in Alzheimer’s disease: more than simple loss of terminals , 2003, Neurobiology of Aging.

[23]  P. Goldman-Rakic,et al.  The reduced neuropil hypothesis: a circuit based model of schizophrenia , 1999, Biological Psychiatry.

[24]  Susumu Ando,et al.  Age‐changes of brain synapses and synaptic plasticity in response to an enriched environment , 1999, Journal of neuroscience research.

[25]  B. Finlay,et al.  Translating developmental time across mammalian species , 2001, Neuroscience.

[26]  J. Altman,et al.  Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. , 1993, Neurotoxicology.

[27]  H. Kaba,et al.  Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses , 1995, FEBS letters.

[28]  R. Hoffman,et al.  Cortical pruning and the development of schizophrenia: a computer model. , 1989, Schizophrenia bulletin.

[29]  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.

[30]  J. Kleinman,et al.  Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia , 2001, Schizophrenia Research.

[31]  Martin H. Teicher,et al.  Delayed Effects of Early Stress on Hippocampal Development , 2004, Neuropsychopharmacology.

[32]  D. Price,et al.  Loss of the Presynaptic Vesicle Protein Synaptophysin in Hippocampus Correlates with Cognitive Decline in Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[33]  D. Born,et al.  Synaptophysin immunocytochemistry with thermal intensification: a marker of terminal axonal maturation in the human fetal nervous system , 1999, Brain and Development.

[34]  P. Goldman-Rakic,et al.  Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. , 1986, Science.

[35]  H. Loos,et al.  Synaptogenesis in human visual cortex — evidence for synapse elimination during normal development , 1982, Neuroscience Letters.

[36]  T. Petit,et al.  Quantifying synaptic number and structure: effects of stain and post-mortem delay , 1990, Brain Research.

[37]  D. Weinberger,et al.  Cell biology of the hippocampal formation in schizophrenia , 1999, Biological Psychiatry.

[38]  P. Greengard,et al.  Antibodies to synaptophysin interfere with transmitter secretion at neuromuscular synapses , 1992, Neuron.

[39]  Paul J. Harrison,et al.  Synaptophysin gene expression in human brain: A quantitative in situ hybridization and immunocytochemical study , 1994, Neuroscience.

[40]  J. Morrison,et al.  Circuit-Specific Alterations in Hippocampal Synaptophysin Immunoreactivity Predict Spatial Learning Impairment in Aged Rats , 2000, The Journal of Neuroscience.

[41]  M. Chechlacz,et al.  Is mental retardation a defect of synapse structure and function? , 2003, Pediatric neurology.

[42]  Margaret Fahnestock,et al.  Kindling and status epilepticus models of epilepsy: rewiring the brain , 2004, Progress in Neurobiology.

[43]  M. Colonnier,et al.  Synaptophysin expression during synaptogenesis in the rat cerebellar cortex , 1989, The Journal of comparative neurology.

[44]  Paul J. Harrison The neuropathology of schizophrenia , 2008 .

[45]  T. Bredy,et al.  Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression , 2004, The European journal of neuroscience.

[46]  P. Rakić,et al.  Tempo of neurogenesis and synaptogenesis in the primate cingulate mesocortex: Comparison with the neocortex , 1995, The Journal of comparative neurology.

[47]  Peter R Mouton,et al.  Empirical assessment of synapse numbers in primate neocortex , 1997, Journal of Neuroscience Methods.

[48]  Paul J. Harrison,et al.  Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections , 1999, Neuroscience.

[49]  W. Honer,et al.  Hippocampal synaptic pathology in patients with temporal lobe epilepsy , 1994, Acta Neuropathologica.

[50]  R. Empson,et al.  Comparison of neuroplastin and synaptic marker protein expression in acute and cultured organotypic hippocampal slices from rat. , 2004, Brain research. Developmental brain research.

[51]  I. Gottesman,et al.  The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia , 2002, BMC psychiatry.

[52]  Paul J. Harrison,et al.  Synaptophysin gene expression in schizophrenia , 2000, British Journal of Psychiatry.

[53]  Karl J. Friston,et al.  Synaptic Plasticity and Dysconnection in Schizophrenia , 2006, Biological Psychiatry.

[54]  H. Romijn,et al.  At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? , 1991, Early human development.

[55]  W. Honer,et al.  Presynaptic proteins and schizophrenia. , 2004, International review of neurobiology.

[56]  P Falkai,et al.  SNAP-25 deficit and hippocampal connectivity in schizophrenia. , 1998, Cerebral cortex.

[57]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[58]  Paul J. Harrison,et al.  Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development , 2005, The European journal of neuroscience.

[59]  M. Gerstein,et al.  Comparing protein abundance and mRNA expression levels on a genomic scale , 2003, Genome Biology.

[60]  P. Huttenlocher,et al.  Regional differences in synaptogenesis in human cerebral cortex , 1997, The Journal of comparative neurology.

[61]  P. Knaus,et al.  Expression of Synaptophysin During Postnatal Development of the Mouse Brain , 1986, Journal of neurochemistry.

[62]  L. Seress,et al.  Cell formation in the human hippocampal formation from mid-gestation to the late postnatal period , 2001, Neuroscience.

[63]  R. Llinás,et al.  Synaptophysin regulates clathrin-independent endocytosis of synaptic vesicles. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  W. Meier-Ruge,et al.  Computer-assisted morphometry of synaptic plasticity during aging and dementia. , 1989, Pathology, research and practice.

[65]  S. Scheff,et al.  Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies , 2003, Neurobiology of Aging.

[66]  S. Anderson,et al.  Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited. , 1994, Journal of psychiatric research.

[67]  T. Voigt,et al.  Synaptophysin immunohistochemistry reveals inside‐out pattern of early synaptogenesis in ferret cerebral cortex , 1993, The Journal of comparative neurology.

[68]  Paul J. Harrison,et al.  Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia , 1998, The Lancet.

[69]  M. Lynch,et al.  Synaptophysin immunogold labelling of synapses decreases in dentate gyrus of the hippocampus of aged rats , 2003, Brain Research.

[70]  J. Kleinman,et al.  Discordant changes in cortical TrkC mRNA and protein during the human lifespan , 2005, The European journal of neuroscience.

[71]  Marc Laruelle,et al.  The Synaptic Hypothesis of Schizophrenia , 2003, Neuron.

[72]  P. Rakić,et al.  Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[73]  E. Masliah,et al.  Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections. , 1990, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[74]  J. Dobbing,et al.  Comparative aspects of the brain growth spurt. , 1979, Early human development.

[75]  E. Masliah,et al.  A simple dot-immunobinding assay for quantification of synaptophysin-like immunoreactivity in human brain. , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[76]  P. Rakić,et al.  A quantitative analysis of synaptogenesis in the molecular layer of the dentate gyrus in the rhesus monkey. , 1991, Brain research. Developmental brain research.

[77]  A. Dekaban,et al.  Changes in brain weights during the span of human life: Relation of brain weights to body heights and body weights , 1978, Annals of neurology.

[78]  Paul J. Harrison,et al.  Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation , 2003, The European journal of neuroscience.

[79]  KM Harris,et al.  Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation [published erratum appears in J Neurosci 1992 Aug;12(8):following table of contents] , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[80]  M. Lynch,et al.  Increase in synaptic vesicle proteins accompanies long-term potentiation in the dentate gyrus , 1994, Neuroscience.

[81]  Roger E Bumgarner,et al.  Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. , 2001, Science.

[82]  T. Shirao,et al.  Differential expression of rat brain synaptic proteins in development and aging. , 1998, Biochemical and biophysical research communications.

[83]  M. Johnston,et al.  Neurobiology of Rett syndrome: a genetic disorder of synapse development , 2001, Brain and Development.

[84]  Paul J. Harrison The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[85]  J. Thibault,et al.  Quantitative Autoradiography of Tyrosine Hydroxylase Immunoreactivity in the Rat Brain , 1991, Journal of neurochemistry.

[86]  N. Uranova,et al.  Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: A postmortem morphometric study , 2005, Synapse.

[87]  T. Woo,et al.  Targeting synapses and myelin in the prevention of schizophrenia , 2005, Schizophrenia Research.

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

[89]  Paul J. Harrison,et al.  Striatal synaptophysin expression and haloperidol-induced synaptic plasticity. , 1994, Neuroreport.

[90]  I. Feinberg,et al.  Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? , 1982, Journal of psychiatric research.

[91]  H. Zoghbi Postnatal Neurodevelopmental Disorders: Meeting at the Synapse? , 2003, Science.

[92]  E. Masliah,et al.  Quantitative synaptic alterations in the human neocortex during normal aging , 1993, Neurology.

[93]  G. Meyer,et al.  Reelin‐expressing neurons in the postnatal and adult human hippocampal formation , 2003, Hippocampus.

[94]  P. Greengard,et al.  Quantitation of nerve terminal populations: Synaptic vesicle‐associated proteins as markers for synaptic density in the rat neostriatum , 1988, Synapse.

[95]  G. Higgins,et al.  Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats , 1999, Brain Research.

[96]  F. Benes,et al.  Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. , 1994, Archives of general psychiatry.

[97]  Diano F. Marrone,et al.  The role of synaptic morphology in neural plasticity: structural interactions underlying synaptic power , 2002, Brain Research Reviews.

[98]  C. Barnstable,et al.  Expression of the growth cone specific epitope CDA 1 and the Synaptic vesicle protein SVP38 in the developing mammalian cerebral cortex , 1989, The Journal of comparative neurology.

[99]  Paul J. Harrison,et al.  Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia , 1995, Neuroscience.

[100]  D. Oorschot,et al.  Are you using neuronal densities, synaptic densities or neurochemical densities as your definitive data? there is a better way to go , 1994, Progress in Neurobiology.

[101]  J. Kleinman,et al.  Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia , 1999, Molecular Psychiatry.