Enhancement of Synaptic Plasticity through Chronically Reduced Ca2+ Flux during Uncorrelated Activity

The plasticity of synapses within neural circuits is regulated by activity, but the underlying mechanisms remain elusive. Using the dye FM1-43 to directly image presynaptic function, we found that large numbers of presynaptic terminals in hippocampal cultures have a low release probability. While these terminals were not readily modifiable, a transient but not permanent long-term reduction of network activity or Ca2+ influx could increase their modifiability. This modulation of plasticity was mediated by Ca2+ flux through NMDA and voltage-gated calcium channels and was lost within 48 hr. A more permanent enhancement of synaptic plasticity was achieved by selectively reducing the Ca2+ flux associated with uncorrelated activity via adjustment of the voltage-dependent Mg2+ block of the NMDAR. Upregulation of NR2B-containing NMDARs induced by this treatment is an important but not sole contributor to the enhancement of plasticity. Thus, quantity and quality of activity have differential effects on the intrinsic plasticity of neurons.

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

[2]  R. Tsien,et al.  Single synaptic vesicles fusing transiently and successively without loss of identity , 2003, Nature.

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

[4]  P. De Camilli,et al.  Chronic Blockade of Glutamate Receptors Enhances Presynaptic Release and Downregulates the Interaction between Synaptophysin-Synaptobrevin–Vesicle-Associated Membrane Protein 2 , 2001, The Journal of Neuroscience.

[5]  T. Schikorski,et al.  Morphological correlates of functionally defined synaptic vesicle populations , 2001, Nature Neuroscience.

[6]  Mark F Bear,et al.  Bidirectional synaptic plasticity: from theory to reality. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[7]  C. Stevens,et al.  An evaluation of causes for unreliability of synaptic transmission. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Ann Marie Craig,et al.  Activity Regulates the Synaptic Localization of the NMDA Receptor in Hippocampal Neurons , 1997, Neuron.

[9]  L. Voronin,et al.  Long-term potentiation in the hippocampus , 1983, Neuroscience.

[10]  A. Woodhull,et al.  Ionic Blockage of Sodium Channels in Nerve , 1973, The Journal of general physiology.

[11]  S. Nelson,et al.  Homeostatic plasticity in the developing nervous system , 2004, Nature Reviews Neuroscience.

[12]  W. Denk,et al.  Dendritic spines as basic functional units of neuronal integration , 1995, Nature.

[13]  M. Mayer,et al.  Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones , 1984, Nature.

[14]  Steven A. Siegelbaum,et al.  Visualization of changes in presynaptic function during long-term synaptic plasticity , 2001, Nature Neuroscience.

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

[16]  E. Kapaki,et al.  Zinc, copper and magnesium concentration in serum and CSF of patients with neurological disorders , 1989, Acta neurologica Scandinavica.

[17]  Stephen J. Smith,et al.  Vesicle pool mobilization during action potential firing at hippocampal synapses , 1995, Neuron.

[18]  G. Westbrook,et al.  Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit , 2000 .

[19]  Richard L. Huganir,et al.  Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons , 1999, Nature Neuroscience.

[20]  Stephen J. Smith,et al.  The kinetics of synaptic vesicle recycling measured at single presynaptic boutons , 1993, Neuron.

[21]  K. Svoboda,et al.  The Life Cycle of Ca2+ Ions in Dendritic Spines , 2002, Neuron.

[22]  J. Lisman.  Bursts as a unit of neural information: making unreliable synapses reliable , 1997, Trends in Neurosciences.

[23]  Guosong Liu,et al.  Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites , 2004, Nature Neuroscience.

[24]  Timothy H. Murphy,et al.  Ca2+ Imaging of CNS Axons in Culture Indicates Reliable Coupling between Single Action Potentials and Distal Functional Release Sites , 1996, Neuron.

[25]  B. Sakmann,et al.  Imaging Synaptic Activity in Intact Brain and Slices with FM1-43 in C. elegans, Lamprey, and Rat , 1999, Neuron.

[26]  M. Crair,et al.  Barrel Cortex Critical Period Plasticity Is Independent of Changes in NMDA Receptor Subunit Composition , 2001, Neuron.

[27]  C. Shatz,et al.  Synaptic Activity and the Construction of Cortical Circuits , 1996, Science.

[28]  D. Hubel,et al.  SINGLE-CELL RESPONSES IN STRIATE CORTEX OF KITTENS DEPRIVED OF VISION IN ONE EYE. , 1963, Journal of neurophysiology.

[29]  L. Maffei,et al.  Functional postnatal development of the rat primary visual cortex and the role of visual experience: Dark rearing and monocular deprivation , 1994, Vision Research.

[30]  G. Bi,et al.  Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type , 1998, The Journal of Neuroscience.

[31]  K. Fox,et al.  A critical period for experience-dependent synaptic plasticity in rat barrel cortex , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  E. Kandel,et al.  Presynaptic BDNF Required for a Presynaptic but Not Postsynaptic Component of LTP at Hippocampal CA1-CA3 Synapses , 2003, Neuron.

[33]  Mu-ming Poo,et al.  Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation , 1999, Nature Neuroscience.

[34]  Mark A. Jervis,et al.  The Life-cycle , 1996 .

[35]  Guosong Liu,et al.  A Developmental Switch in Neurotransmitter Flux Enhances Synaptic Efficacy by Affecting AMPA Receptor Activation , 2001, Neuron.

[36]  R. Tsien,et al.  Variability of Neurotransmitter Concentration and Nonsaturation of Postsynaptic AMPA Receptors at Synapses in Hippocampal Cultures and Slices , 1999, Neuron.

[37]  M. Bear,et al.  Metaplasticity: the plasticity of synaptic plasticity , 1996, Trends in Neurosciences.

[38]  R. Carretta,et al.  Cerebrospinal fluid and serum levels of magnesium, zinc, and calcium in man , 1968, Neurology.

[39]  T. Schikorski,et al.  Inactivity Produces Increases in Neurotransmitter Release and Synapse Size , 2001, Neuron.

[40]  S. Vicini,et al.  Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. , 1998, Journal of neurophysiology.

[41]  G. Westbrook,et al.  Fast NMDA receptor-mediated synaptic currents in neurons from mice lacking the epsilon2 (NR2B) subunit. , 2000, Journal of neurophysiology.

[42]  E. Schuman,et al.  Neurotrophins and Time: Different Roles for TrkB Signaling in Hippocampal Long-Term Potentiation , 1997, Neuron.

[43]  D. Mitchell,et al.  The development of vision in cats after extended periods of dark-rearing , 1978, Experimental Brain Research.

[44]  Bai Lu,et al.  BDNF and activity-dependent synaptic modulation. , 2003, Learning & memory.

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

[46]  A. Konnerth,et al.  NMDA Receptor-Mediated Subthreshold Ca2+ Signals in Spines of Hippocampal Neurons , 2000, The Journal of Neuroscience.

[47]  L. Nowak,et al.  Magnesium gates glutamate-activated channels in mouse central neurones , 1984, Nature.

[48]  Venkatesh N. Murthy,et al.  Synaptic vesicles retain their identity through the endocytic cycle , 1998, Nature.

[49]  W. Betz,et al.  Activity-dependent fluorescent staining and destaining of living vertebrate motor nerve terminals , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  D. Shelton,et al.  Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[52]  C. Gilbert,et al.  The Neural Basis of Perceptual Learning , 2001, Neuron.

[53]  R. Tsien,et al.  α- and βCaMKII Inverse Regulation by Neuronal Activity and Opposing Effects on Synaptic Strength , 2002, Neuron.

[54]  M. Stryker,et al.  Binocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  CE Jahr,et al.  A quantitative description of NMDA receptor-channel kinetic behavior , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  J. Chutkow,et al.  Metabolism of magnesium in central nervous system , 1974, Neurology.

[57]  R. Tsien,et al.  alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing effects on synaptic strength. , 2002, Neuron.

[58]  M. Stryker,et al.  Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. , 1988, Science.

[59]  C. Stevens,et al.  Calcium permeability of the N-methyl-D-aspartate receptor channel in hippocampal neurons in culture. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[60]  T. Sejnowski,et al.  Heterogeneous Release Properties of Visualized Individual Hippocampal Synapses , 1997, Neuron.

[61]  Hisashi Mori,et al.  Separable features of visual cortical plasticity revealed by N-methyl-d-aspartate receptor 2A signaling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[62]  G. Dubé,et al.  High-resolution iontophoresis for single-synapse stimulation , 2002, Journal of Neuroscience Methods.

[63]  D. Buonomano,et al.  Cortical plasticity: from synapses to maps. , 1998, Annual review of neuroscience.

[64]  M. Mayer,et al.  Permeation and block of N‐methyl‐D‐aspartic acid receptor channels by divalent cations in mouse cultured central neurones. , 1987, The Journal of physiology.

[65]  J. Lisman,et al.  A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[66]  G. Carmignoto,et al.  Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. , 1992, Science.

[67]  H. Lester,et al.  Enhancement of Neurotransmitter Release Induced by Brain-Derived Neurotrophic Factor in Cultured Hippocampal Neurons , 1998, The Journal of Neuroscience.

[68]  S. J. Smith,et al.  The timing of synaptic vesicle endocytosis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Edward F Chang,et al.  Environmental Noise Retards Auditory Cortical Development , 2003, Science.

[70]  G. Shepherd,et al.  Single‐axon action potentials in the rat hippocampal cortex , 2003, The Journal of physiology.