Burst-Dependent Bidirectional Plasticity in the Cerebellum Is Driven by Presynaptic NMDA Receptors.

Numerous studies have shown that cerebellar function is related to the plasticity at the synapses between parallel fibers and Purkinje cells. How specific input patterns determine plasticity outcomes, as well as the biophysics underlying plasticity of these synapses, remain unclear. Here, we characterize the patterns of activity that lead to postsynaptically expressed LTP using both in vivo and in vitro experiments. Similar to the requirements of LTD, we find that high-frequency bursts are necessary to trigger LTP and that this burst-dependent plasticity depends on presynaptic NMDA receptors and nitric oxide (NO) signaling. We provide direct evidence for calcium entry through presynaptic NMDA receptors in a subpopulation of parallel fiber varicosities. Finally, we develop and experimentally verify a mechanistic plasticity model based on NO and calcium signaling. The model reproduces plasticity outcomes from data and predicts the effect of arbitrary patterns of synaptic inputs on Purkinje cells, thereby providing a unified description of plasticity.

[1]  Masao Ito,et al.  Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex , 1982, Neuroscience Letters.

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

[3]  C. Hansel,et al.  Bidirectional Parallel Fiber Plasticity in the Cerebellum under Climbing Fiber Control , 2004, Neuron.

[4]  John A. Nelder,et al.  A Simplex Method for Function Minimization , 1965, Comput. J..

[5]  M. Ito,et al.  Messengers mediating long-term desensitization in cerebellar Purkinje cells. , 1990, Neuroreport.

[6]  R. Nicoll,et al.  Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus. , 1993, Journal of neurophysiology.

[7]  J. Garthwaite,et al.  Long‐Term Depression in Rat Cerebellum Requires both NO Synthase and NO‐sensitive Guanylyl Cyclase , 1996, The European journal of neuroscience.

[8]  David Attwell,et al.  Short‐ and long‐term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk , 2007, The Journal of physiology.

[9]  K. Mikoshiba,et al.  Short-term potentiation at the parallel fiber–Purkinje cell synapse , 2006, Neuroscience Research.

[10]  Nicolas Brunel,et al.  Optimal Properties of Analog Perceptrons with Excitatory Weights , 2013, PLoS Comput. Biol..

[11]  M. Häusser,et al.  Integration of quanta in cerebellar granule cells during sensory processing , 2004, Nature.

[12]  Boris Barbour,et al.  Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule , 2009, Proceedings of the National Academy of Sciences.

[13]  D. Attwell,et al.  Non‐synaptic Release of ATP by Electrical Stimulation in Slices of Rat Hippocampus, Cerebellum and Habenula , 1996, The European journal of neuroscience.

[14]  T. Ebner,et al.  Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo , 2009, Neuroscience.

[15]  Donata Oertel,et al.  Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Jung Hoon Shin,et al.  An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. , 2005, Journal of neurophysiology.

[17]  C. Levenes,et al.  NMDA Receptor Contribution to the Climbing Fiber Response in the Adult Mouse Purkinje Cell , 2007, The Journal of Neuroscience.

[18]  G. Kohr,et al.  NR2A subunit of the N-methyl d-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning , 2011, Neuroscience.

[19]  S Kawahara,et al.  Conditioned eyeblink response is impaired in mutant mice lacking NMDA receptor subunit NR2A , 1997, Neuroreport.

[20]  M. Kawato,et al.  Ca2+ Requirements for Cerebellar Long-Term Synaptic Depression: Role for a Postsynaptic Leaky Integrator , 2007, Neuron.

[21]  L. Cooper,et al.  A unified model of NMDA receptor-dependent bidirectional synaptic plasticity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Ole Paulsen,et al.  Spike timing–dependent long-term depression requires presynaptic NMDA receptors , 2008, Nature Neuroscience.

[23]  B. Barbour,et al.  Properties of Unitary Granule Cell→Purkinje Cell Synapses in Adult Rat Cerebellar Slices , 2002, The Journal of Neuroscience.

[24]  Marco Canepari,et al.  Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP , 2008, PloS one.

[25]  Roger Y Tsien,et al.  A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Shigeyuki Namiki,et al.  NO signalling decodes frequency of neuronal activity and generates synapse‐specific plasticity in mouse cerebellum , 2005, The Journal of physiology.

[27]  Laure Rondi-Reig,et al.  T-type channel blockade impairs long-term potentiation at the parallel fiber–Purkinje cell synapse and cerebellar learning , 2013, Proceedings of the National Academy of Sciences.

[28]  Benjamin Mathieu,et al.  Optical monitoring of neuronal activity at high frame rate with a digital random-access multiphoton (RAMP) microscope , 2008, Journal of Neuroscience Methods.

[29]  Henrik Jörntell,et al.  Synaptic Memories Upside Down: Bidirectional Plasticity at Cerebellar Parallel Fiber-Purkinje Cell Synapses , 2006, Neuron.

[30]  R. Tsien,et al.  Synergies and Coincidence Requirements between NO, cGMP, and Ca2+ in the Induction of Cerebellar Long-Term Depression , 1997, Neuron.

[31]  Philippe Isope,et al.  Involvement of Presynaptic N-Methyl-D-Aspartate Receptors in Cerebellar Long-Term Depression , 2002, Neuron.

[32]  Wulfram Gerstner,et al.  A neuronal learning rule for sub-millisecond temporal coding , 1996, Nature.

[33]  S. Palay,et al.  Cerebellar Cortex: Cytology and Organization , 1974 .

[34]  Y. Dan,et al.  Spike-timing-dependent synaptic modification induced by natural spike trains , 2002, Nature.

[35]  S. Snyder,et al.  Localization of nitric oxide synthase indicating a neural role for nitric oxide , 1990, Nature.

[36]  P. J. Sjöström,et al.  Neocortical LTD via Coincident Activation of Presynaptic NMDA and Cannabinoid Receptors , 2003, Neuron.

[37]  E. Kandel,et al.  Memory: From Mind to Molecules , 1999 .

[38]  M. Mishina,et al.  Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release. , 2016, Journal of neurophysiology.

[39]  George J. Augustine,et al.  Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites , 1998, Nature.

[40]  Alessandro Alabastri,et al.  High-performance and site-directed in utero electroporation with a triple-electrode probe , 2012, Nature Communications.

[41]  J. Rawlins,et al.  Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus , 2007, The European journal of neuroscience.

[42]  C. Hansel,et al.  Purkinje Cell NMDA Receptors Assume a Key Role in Synaptic Gain Control in the Mature Cerebellum , 2010, The Journal of Neuroscience.

[43]  C. Hansel,et al.  A Role for Protein Phosphatases 1, 2A, and 2B in Cerebellar Long-Term Potentiation , 2005, The Journal of Neuroscience.

[44]  Jasper Akerboom,et al.  Optimization of a GCaMP Calcium Indicator for Neural Activity Imaging , 2012, The Journal of Neuroscience.

[45]  H. Monyer,et al.  Cerebellar granule cell Cre recombinase expression , 2003, Genesis.

[46]  S. Wang,et al.  Coincidence detection in single dendritic spines mediated by calcium release , 2000, Nature Neuroscience.

[47]  Wade G. Regehr,et al.  Timing dependence of the induction of cerebellar LTD , 2008, Neuropharmacology.

[48]  G. Schwarz.  Estimating the Dimension of a Model , 1978 .

[49]  D. Debanne,et al.  Asynchronous pre- and postsynaptic activity induces associative long-term depression in area CA1 of the rat hippocampus in vitro. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P. Ascher,et al.  High-Affinity Zinc Inhibition of NMDA NR1–NR2A Receptors , 1997, The Journal of Neuroscience.

[51]  P. J. Sjöström,et al.  Rate, Timing, and Cooperativity Jointly Determine Cortical Synaptic Plasticity , 2001, Neuron.

[52]  W. Lim,et al.  PSD-95 Assembles a Ternary Complex with theN-Methyl-d-aspartic Acid Receptor and a Bivalent Neuronal NO Synthase PDZ Domain* , 1999, The Journal of Biological Chemistry.

[53]  Yihui Cui,et al.  Distinct coincidence detectors govern the corticostriatal spike timing‐dependent plasticity , 2010, The Journal of physiology.

[54]  Dong Yang,et al.  Long-Term Potentiation at Cerebellar Parallel Fiber–Purkinje Cell Synapses Requires Presynaptic and Postsynaptic Signaling Cascades , 2014, The Journal of Neuroscience.

[55]  Vanessa A. Bender,et al.  Two Coincidence Detectors for Spike Timing-Dependent Plasticity in Somatosensory Cortex , 2006, The Journal of Neuroscience.

[56]  K. Schermelleh-Engel,et al.  Evaluating the Fit of Structural Equation Models: Tests of Significance and Descriptive Goodness-of-Fit Measures. , 2003 .

[57]  H. Akaike.  A new look at the statistical model identification , 1974 .

[58]  C. Bidoret,et al.  Properties and molecular identity of NMDA receptors at synaptic and non-synaptic inputs in cerebellar molecular layer interneurons , 2015, Front. Synaptic Neurosci..

[59]  J. Rawson,et al.  Morphology of parallel fibres in the cerebellar cortex of the rat: An experimental light and electron microscopic study with biocytin , 1994, The Journal of comparative neurology.

[60]  P. Bearman,et al.  Correction for Graupner and Brunel, Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location , 2012, Proceedings of the National Academy of Sciences.