Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1.

Long-term potentiation (LTP) of the Schaffer collateral/commissural inputs to CA1 in the hippocampus was shown to consist of N-methyl-D-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) dependent forms. In this study, the relative contributions of these two forms of LTP in in vitro hippocampal slices from young (2 mo) and old (24 mo) Fischer 344 rats were examined. Excitatory postsynaptic potentials (EPSP) were recorded extracellularly from stratum radiatum before and after a tetanic stimulus consisting of four 200-Hz, 0.5-s trains given 5 s apart. Under control conditions, a compound LTP consisting of both forms was induced and was similar, in both time course and magnitude, in young and old animals. NMDAR-dependent LTP (nmdaLTP), isolated by the application of 10 microM nifedipine (a voltage-dependent calcium channel blocker), was significantly reduced in magnitude in aged animals. The VDCC dependent form (vdccLTP), isolated by the application of 50 microM D,L-2-amino-5-phosphonvalerate (APV), was significantly larger in aged animals. Although both LTP forms reached stable values 40-60 min posttetanus in young animals, in aged animals vdccLTP increased and nmdaLTP decreased during this time. In both young and old animals, the sum of the two isolated LTP forms approximated the magnitude of the compound LTP, and application of APV and nifedipine or genestein (a tyrosine kinase inhibitor) together blocked potentiation. These results suggest that aging causes a shift in synaptic plasticity from NMDAR-dependent mechanisms to VDCC-dependent mechanisms. The data are consistent with previous findings of increased L-type calcium current and decreased NMDAR number in aged CA1 cells and may help explain age-related deficits in learning and memory.

[1]  C. Cotman,et al.  Age-related changes in excitatory amino acid receptors in two mouse strains , 1993, Neurobiology of Aging.

[2]  T. Teyler,et al.  Two forms of long-term potentiation in area CA1 activate different signal transduction cascades. , 1996, Journal of neurophysiology.

[3]  Acknowledgements WethankDavid.  Normal aging: regionally specific changes in hippocampal synaptic transmission , 1994 .

[4]  P. Landfield.  ‘Increased calcium-current’ hypothesis of brain aging , 1987, Neurobiology of Aging.

[5]  D. Price,et al.  Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys , 1991, Neurobiology of Aging.

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

[7]  B. McNaughton,et al.  Hippocampal synaptic enhancement and information storage within a distributed memory system , 1987, Trends in Neurosciences.

[8]  P. Landfield,et al.  Aging-related prolongation of calcium spike duration in rat hippocampal slice neurons , 1990, Brain Research.

[9]  N. Robbins.  Compensatory plasticity of aging at the neuromuscular junction , 1992, Experimental Gerontology.

[10]  W. Greenough,et al.  Synapse formation occurs in association with the induction of long-term potentiation in two-year-old rat hippocampus in vitro , 1991, Neurobiology of Aging.

[11]  B. McNaughton,et al.  Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats. , 1996, Learning & memory.

[12]  J. Eccles.  Hippocampal plasticity. , 1979, Progress in brain research.

[13]  A. Keller,et al.  Mechanisms of LTP induction in rat motor cortex in vitro. , 1995, Cerebral cortex.

[14]  C. Cotman,et al.  In vitro autoradiography of hippocampal excitatory amino acid binding in aged Fischer 344 rats: relationship to performance on the Morris water maze. , 1992, Behavioral neuroscience.

[15]  Gordon Winocur,et al.  A comparison of normal old rats and young adult rats with lesions to the hippocampus or prefrontal cortex on a test of matching-to-sample , 1992, Neuropsychologia.

[16]  A. Maillis,et al.  Dihydropyridine-sensitive calcium channels are involved in the induction of N-methyl-d-aspartate receptor-independent long-term potentiation in visual cortex of adult rats , 1993, Neuroscience Letters.

[17]  P. Landfield,et al.  Corticosteroid modulation of hippocampal potentials: increased effect with aging. , 1989, Science.

[18]  D. Turner,et al.  Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats , 1991, Brain Research.

[19]  A. J. Hill.  First occurrence of hippocampal spatial firing in a new environment , 1978, Experimental Neurology.

[20]  V. Gribkoff,et al.  Age-dependence of effects of A1 adenosine receptor antagonism in rat hippocampal slices. , 1992, Journal of neurophysiology.

[21]  Lawrence M. Grover,et al.  Two components of long-term potentiation induced by different patterns of afferent activation , 1990, Nature.

[22]  J F Disterhoft,et al.  Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner. , 1992, Journal of neurophysiology.

[23]  Y. Komatsu.  Plasticity of excitatory synaptic transmission in kitten visual cortex depends on voltage-dependent Ca2+ channels but not on NMDA receptors , 1994, Neuroscience Research.

[24]  F. Gage,et al.  Hippocampal connections and spatial discrimination , 1978, Brain Research.

[25]  T. Teyler,et al.  N-methyl-d-aspartate receptor-independent long-term potentiation in area CA1 of rat hippocampus: Input-specific induction and preclusion in a non-tetanized pathway , 1992, Neuroscience.

[26]  T. Teyler,et al.  Activation of NMDA receptors in hippocampal area CA1 by low and high frequency orthodromic stimulation and their contribution to induction of long‐term potentiation , 1994, Synapse.

[27]  K. Harris,et al.  Developmental onset of long‐term potentiation in area CA1 of the rat hippocampus. , 1984, The Journal of physiology.

[28]  P. Landfield.  Increased Hippocampal Ca2+ Channel Activity in Brain Aging and Dementia , 1994, Annals of the New York Academy of Sciences.

[29]  G. Rose,et al.  Hippocampal plasticity induced by primed burst, but not long‐term potentiation, stimulation is impaired in area CA1 of aged fischer 344 rats , 1993, Hippocampus.

[30]  R. Sutherland,et al.  A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat , 1983, Behavioural Brain Research.

[31]  Z. Khachaturian.  The role of calcium regulation in brain aging: reexamination of a hypothesis , 1989, Aging.

[32]  Michael C. Crair,et al.  A critical period for long-term potentiation at thalamocortical synapses , 1995, Nature.

[33]  M E Greenberg,et al.  Calcium signaling in neurons: molecular mechanisms and cellular consequences. , 1995, Science.

[34]  A. Karppinen,et al.  Amino acids in the synaptic vesicle fraction from calf brain: content, uptake and metabolism , 1977, Brain Research.

[35]  M. Shibuya,et al.  Genistein, a specific inhibitor of tyrosine-specific protein kinases. , 1987, The Journal of biological chemistry.

[36]  J. Meldolesi,et al.  Cytosolic Ca2+ Binding Proteins during Rat Brain Ageing: Loss of Calbindin and Calretinin in the Hippocampus, with no Change in the Cerebellum , 1994, The European journal of neuroscience.

[37]  S. Kirischuk,et al.  Age‐Dependent Changes in Calcium Currents and Calcium Homeostasis in Mammalian Neurons a , 1994, Annals of the New York Academy of Sciences.

[38]  J. Disterhoft,et al.  Nimodipine decreases calcium action potentials in rabbit hippocampal CA1 neurons in an age‐dependent and concentration‐dependent manner , 1994, Hippocampus.

[39]  T. Teyler,et al.  Long-term potentiation. , 1987, Annual review of neuroscience.

[40]  B. Connors,et al.  THALAMOCORTICAL SYNAPSES , 1997, Progress in Neurobiology.

[41]  J. Disterhoft,et al.  Relation of Nimodipine Dose and Serum Concentration to Learning Enhancement in Aging Rabbits , 1994, Experimental Neurology.

[42]  SM Dudek,et al.  Bidirectional long-term modification of synaptic effectiveness in the adult and immature hippocampus , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[43]  Mark F. Bear,et al.  Co-regulation of long-term potentiation and experience-dependent synaptic plasticity in visual cortex by age and experience , 1995, Nature.

[44]  Timothy J. Teyler,et al.  Long-term potentiation as a candidate mnemonic device , 1984, Brain Research Reviews.

[45]  G. Gibson,et al.  Calcium and the aging nervous system , 1987, Neurobiology of Aging.

[46]  J. D. McGaugh,et al.  Impaired synaptic potentiation processes in the hippocampus of aged, memory-deficient rats , 1978, Brain Research.

[47]  Lawrence M. Grover,et al.  An integrated multielectrode electrophysiology system , 1991, Journal of Neuroscience Methods.

[48]  E. Kandel,et al.  Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors , 1991, Nature.

[49]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[50]  C. Barnes.  Normal aging: regionally specific changes in hippocampal synaptic transmission , 1994, Trends in Neurosciences.

[51]  K. Harris,et al.  The development of long-term potentiation in hippocampus and neocortex , 1989, Neuropsychologia.

[52]  G. Buzsáki,et al.  Differential contribution of fimbria and fornix fibers to behavior. , 1980, Behavioral and neural biology.

[53]  Philip W. Landfield,et al.  Increase in Single L-Type Calcium Channels in Hippocampal Neurons During Aging , 1996, Science.

[54]  D. Turner,et al.  Age-related alterations in potentiation in the CA1 region in F344 rats , 1993, Neurobiology of Aging.

[55]  D. Olton,et al.  Spatial correlates of hippocampal unit activity , 1978, Experimental Neurology.

[56]  J F Disterhoft,et al.  The Calcium Rationale in Aging and Alzheimer's Disease , 1994, Annals of the New York Academy of Sciences.

[57]  M. Fahim,et al.  Ultrastructural studies of young and old mouse neuromuscular junctions , 1982, Journal of neurocytology.

[58]  C. Barnes,et al.  Acetyl-l-carnitine: Behavioral, electrophysiological, and neurochemical effects , 1993, Neurobiology of Aging.

[59]  M Moscovitch,et al.  Hippocampal and prefrontal cortex contributions to learning and memory: analysis of lesion and aging effects on maze learning in rats. , 1990, Behavioral neuroscience.

[60]  Lucien T. Thompson,et al.  Nimodipine enhances spontaneous activity of hippocampal pyramidal neurons in aging rabbits at a dose that facilitates associative learning , 1990, Brain Research.

[61]  Eric R. Kandel,et al.  The neuroscience of learning and memory: cells, neural circuits and behavior , 1988, Trends in Neurosciences.

[62]  M. Michaelis.  Ion Transport Systems and Ca2+ Regulation in Aging Neurons , 1994, Annals of the New York Academy of Sciences.

[63]  C. Cotman,et al.  Effects of aging on NMDA and MK801 binding sites in mice , 1993, Brain Research.

[64]  M E Greenberg,et al.  Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. , 1993, Science.

[65]  D. Cain,et al.  Spatial learning without NMDA receptor-dependent long-term potentiation , 1995, Nature.

[66]  E. Cherubini,et al.  Developmental Shift From Long‐term Depression to Long‐term Potentiation at the Mossy Fibre Synapses in the Rat Hippocampus , 1994, The European journal of neuroscience.

[67]  Y. Yoneda,et al.  Age-related decreases of the N-methyl-d-aspartate receptor complex in the rat cerebral cortex and hippocampus , 1991, Brain Research.

[68]  T. A. Pitler,et al.  Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. , 1984, Science.

[69]  Lee W. Campbell,et al.  Aging Changes in Voltage-Gated Calcium Currents in Hippocampal CA1 Neurons , 1996, The Journal of Neuroscience.

[70]  Z. Khachaturian.  Calcium Hypothesis of Alzheimer's Disease and Brain Aging a , 1994, Annals of the New York Academy of Sciences.