A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor

Cardiac function is modulated by norepinephrine release from innervating sympathetic neurons. These neurons also form excitatory connections onto cardiac myocytes in culture. Here we report that brain-derived neurotrophic factor (BDNF) altered the neurotransmitter release properties of these sympathetic neuron-myocyte connections in rodent cell culture, leading to a rapid shift from excitatory to inhibitory cholinergic transmission in response to neuronal stimulation. Fifteen minutes of BDNF perfusion was sufficient to cause this shift to inhibitory transmission, indicating that BDNF promotes preferential release of acetylcholine in response to neuronal stimulation. We found that p75−/− neurons did not release acetylcholine in response to BDNF and that neurons overexpressing p75 showed increased cholinergic transmission, indicating that the actions of BDNF are mediated through the p75 neurotrophin receptor. Our findings indicate that p75 is involved in modulating the release of distinct neurotransmitter pools, resulting in a functional switch between excitatory and inhibitory neurotransmission in individual neurons.

[1]  D. Potter,et al.  Chemical transmission between rat sympathetic neurons and cardiac myocytes developing in microcultures: evidence for cholinergic, adrenergic, and dual-function neurons. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[2]  G. Yancopoulos,et al.  The low affinity NGF receptor, p75, can collaborate with each of the Trks to potentiate functional responses to the neurotrophins , 1994, Neuron.

[3]  P. Barker,et al.  Extended Ceramide Exposure Activates the trkA Receptor by Increasing Receptor Homodimer Formation , 1999, Journal of neurochemistry.

[4]  L. Conforti,et al.  Influence of sympathetic innervation on the membrane electrical properties of neonatal rat cardiomyocytes in culture. , 1991, Journal of developmental physiology.

[5]  T. Südhof.  alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins. , 2001, Annual review of neuroscience.

[6]  D. Martin,et al.  Cytosine arabinoside kills postmitotic neurons in a fashion resembling trophic factor deprivation: evidence that a deoxycytidine-dependent process may be required for nerve growth factor signal transduction , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  E. Salido,et al.  Colocalization of tyrosine hydroxylase and GAD65 mRNA in mesostriatal neurons , 2001, The European journal of neuroscience.

[8]  Nancy Y. Ip,et al.  Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF , 1993, Nature.

[9]  H. Hatanaka,et al.  Neurotrophin-elicited short-term glutamate release from cultured cerebellar granule neurons , 1999, Brain Research.

[10]  D. Kaplan,et al.  The TrkB-Shc Site Signals Neuronal Survival and Local Axon Growth via MEK and PI3-Kinase , 2000, Neuron.

[11]  R. Dobrowsky,et al.  Activation of the sphingomyelin cycle through the low-affinity neurotrophin receptor. , 1994, Science.

[12]  Barbara L. Hempstead,et al.  Regulation of Cell Survival by Secreted Proneurotrophins , 2001, Science.

[13]  D. Potter,et al.  Synaptic functions in rat sympathetic neurons in microcultures. I. Secretion of norepinephrine and acetylcholine , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  M. Poo,et al.  Synaptic Modulation by Neurotrophic Factors: Differential and Synergistic Effects of Brain-Derived Neurotrophic Factor and Ciliary Neurotrophic Factor , 1996, The Journal of Neuroscience.

[15]  P. Patterson,et al.  Role of nerve growth factor in the development of rat sympathetic neurons in vitro. III. Effect on acetylcholine production , 1977, The Journal of cell biology.

[16]  P. Jonas,et al.  Corelease of two fast neurotransmitters at a central synapse. , 1998, Science.

[17]  W. Tyler,et al.  BDNF Enhances Quantal Neurotransmitter Release and Increases the Number of Docked Vesicles at the Active Zones of Hippocampal Excitatory Synapses , 2001, The Journal of Neuroscience.

[18]  C. Sirrenberg,et al.  Neurotrophins Stimulate the Release of Dopamine from Rat Mesencephalic Neurons via Trk and p75Lntr Receptors* , 1996, The Journal of Biological Chemistry.

[19]  H. Schnürch,et al.  Neurotrophin-3 promotes the cholinergic differentiation of sympathetic neurons. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Pozniak,et al.  The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death , 1998, The Journal of cell biology.

[21]  G G Turrigiano,et al.  Nerve Growth Factor Modulates Synaptic Transmission between Sympathetic Neurons and Cardiac Myocytes , 1997, The Journal of Neuroscience.

[22]  R. Dobrowsky,et al.  Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75 , 1996, Nature.

[23]  David J. Anderson,et al.  p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells , 1994, Neuron.

[24]  L C Katz,et al.  Neurotrophins and synaptic plasticity. , 1999, Annual review of neuroscience.

[25]  J. Mead,et al.  Nerve growth factor collaborates with myocyte-derived factors to promote development of presynaptic sites in cultured sympathetic neurons. , 2000, Journal of neurobiology.

[26]  S. Landis,et al.  Evidence for neurotransmitter plasticity in vivo: developmental changes in properties of cholinergic sympathetic neurons. , 1983, Developmental biology.

[27]  Yasuhisa Endo,et al.  Brain‐Derived Neurotrophic Factor Increases the Stimulation‐Evoked Release of Glutamate and the Levels of Exocytosis‐Associated Proteins in Cultured Cortical Neurons from Embryonic Rats , 1997, Journal of neurochemistry.

[28]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[29]  P. Barker,et al.  Transgenic Mice Expressing the Intracellular Domain of the p75 Neurotrophin Receptor Undergo Neuronal Apoptosis , 1997, The Journal of Neuroscience.

[30]  H. Thoenen,et al.  Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. S. Sloviter,et al.  Basal expression and induction of glutamate decarboxylase GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus , 1996, The Journal of comparative neurology.

[32]  B. Lu,et al.  Presynaptic Modulation of Synaptic Transmission and Plasticity by Brain-Derived Neurotrophic Factor in the Developing Hippocampus , 1998, The Journal of Neuroscience.

[33]  David R Kaplan,et al.  Neurotrophin signal transduction in the nervous system , 2000, Current Opinion in Neurobiology.

[34]  D. Sulzer,et al.  Dale's principle and glutamate corelease from ventral midbrain dopamine neurons , 2000, Amino Acids.

[35]  M. Barbacid,et al.  TrkB and TrkC Signaling Are Required for Maturation and Synaptogenesis of Hippocampal Connections , 1998, The Journal of Neuroscience.

[36]  S. Haber,et al.  Dopamine Neurons Make Glutamatergic Synapses In Vitro , 1998, The Journal of Neuroscience.

[37]  H. Rohrer,et al.  Ciliary neurotrophic factor induces cholinergic differentiation of rat sympathetic neurons in culture , 1989, The Journal of cell biology.

[38]  V. Ferrans,et al.  Nerve Growth Factor (NGF)-induced Calcium Influx and Intracellular Calcium Mobilization in 3T3 Cells Expressing NGF Receptors* , 1999, The Journal of Biological Chemistry.

[39]  M. Schäfer,et al.  Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Higgins,et al.  Rapid changes in synaptic vesicle cytochemistry after depolarization of cultured cholinergic sympathetic neurons , 1985, The Journal of cell biology.

[41]  P. Patterson,et al.  ROLE OF NERVE GROWTH FACTOR IN THE OF RAT SYMPATHETIC NEURONS IN VITRO , 2003 .

[42]  S. Landis.  Rat sympathetic neurons and cardiac myocytes developing in microcultures: correlation of the fine structure of endings with neurotransmitter function in single neurons. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Kullmann,et al.  Monosynaptic GABAergic Signaling from Dentate to CA3 with a Pharmacological and Physiological Profile Typical of Mossy Fiber Synapses , 2001, Neuron.

[44]  D. Potter,et al.  Synaptic functions in rat sympathetic neurons in microcultures. II. Adrenergic/cholinergic dual status and plasticity , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  W. De Potter,et al.  Noradrenaline Storing Vesicles in Sympathetic Neurons and Their Putative Role in Neurotransmitter Release: An Historical Overview of Controversial Issues , 1997, Neurochemical Research.

[46]  R. Stephens,et al.  The Cytoplasmic and Transmembrane Domains of the p75 and Trk A Receptors Regulate High Affinity Binding to Nerve Growth Factor* , 2001, The Journal of Biological Chemistry.

[47]  M. Chao,et al.  Disruption of cysteine-rich repeats of the p75 nerve growth factor receptor leads to loss of ligand binding. , 1991, The Journal of biological chemistry.

[48]  R. Wenthold,et al.  Neurotrophins act at presynaptic terminals to activate synapses among cultured hippocampal neurons , 2001, The European journal of neuroscience.

[49]  A. Fagan,et al.  TrkA, But Not TrkC, Receptors Are Essential for Survival of Sympathetic Neurons In Vivo , 1996, The Journal of Neuroscience.

[50]  M. Chao,et al.  Competitive Signaling Between TrkA and p75 Nerve Growth Factor Receptors Determines Cell Survival , 1998, The Journal of Neuroscience.

[51]  R. Jaenisch,et al.  Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system , 1992, Cell.