Serotonin Stimulates Phosphorylation of AplysiaSynapsin and Alters Its Subcellular Distribution in Sensory Neurons

Only a small fraction of neurotransmitter-containing synaptic vesicles (SVs), the readily releasable pool, is available for fast Ca2+-induced release at any synapse. Most SVs are sequestered at sites away from the plasma membrane and cannot be exocytosed directly. Recruitment of SVs to the releasable pool is thought to be an important component of short-term synaptic facilitation by serotonin (5-HT) at Aplysia sensorimotor synapses. Synapsins are associated with SVs and hypothesized to play a central role in the regulation of SV mobilization in nerve terminals.Aplysia synapsin was cloned to examine its role in synaptic plasticity at the well characterized sensorimotor neuron synapse of this animal. Acute 5-HT treatment of ganglia induced synapsin phosphorylation. Immunohistochemical analyses of culturedAplysia neurons revealed that synapsin is distributed in distinct puncta in the neurites. These puncta are rapidly dispersed after treatment of the neurons with 5-HT. The dispersion of synapsin puncta by 5-HT was fully reversible after washout of the modulator. Both 5-HT-induced phosphorylation and dispersion of synapsin were mediated, at least in part, by cAMP-dependent protein kinase and mitogen-activated protein kinase. These experiments indicate that synapsin and its regulation by 5-HT may play an important role in the modulation of SV trafficking in short-term synaptic plasticity.

[1]  E R Kandel,et al.  Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Greengard,et al.  Interaction of free and synaptic vesicle-bound synapsin I with F-actin , 1992, Neuron.

[3]  P. Greengard,et al.  Interactions of synapsin I with small synaptic vesicles: distinct sites in synapsin I bind to vesicle phospholipids and vesicle proteins , 1989, The Journal of cell biology.

[4]  N Dale,et al.  Second messengers involved in the two processes of presynaptic facilitation that contribute to sensitization and dishabituation in Aplysia sensory neurons. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Burgoyne,et al.  Protein phosphorylation and the regulation of synaptic membrane traffic , 1999, Trends in Neurosciences.

[6]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[7]  P. Greengard,et al.  Two sites of action for synapsin domain E in regulating neurotransmitter release , 1998, Nature Neuroscience.

[8]  J. Sangerman,et al.  The domain of brain β-spectrin responsible for synaptic vesicle association is essential for synaptic transmission , 2000, Brain Research.

[9]  D. A. Baxter,et al.  Involvement of protein kinase C in serotonin-induced spike broadening and synaptic facilitation in sensorimotor connections of Aplysia. , 1992, Journal of neurophysiology.

[10]  B. Morris,et al.  Induction of c-fos and zif/268 gene expression in rat striatal neurons, following stimulation of D1-like dopamine receptors, involves protein kinase A and protein kinase C , 1995, Neuroscience.

[11]  P. Greengard,et al.  Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Michael A Sutton,et al.  Parallel Molecular Pathways Mediate Expression of Distinct Forms of Intermediate-Term Facilitation at Tail Sensory–Motor Synapses in Aplysia , 2000, Neuron.

[13]  S. Schacher,et al.  Neurite regeneration by Aplysia neurons in dissociated cell culture: modulation by Aplysia hemolymph and the presence of the initial axonal segment , 1983, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  M. Ghirardi,et al.  Synapsin‐like Molecules in Aplysia punctata and Helix pomatia: Identification and Distribution in the Nervous System and During the Formation of Synaptic Contacts In Vitro , 1996, The European journal of neuroscience.

[15]  J. Byrne,et al.  Simulation of synaptic depression, posttetanic potentiation, and presynaptic facilitation of synaptic potentials from sensory neurons mediating gill-withdrawal reflex in Aplysia. , 1985, Journal of neurophysiology.

[16]  J. Byrne,et al.  Analysis of synaptic depression contributing to habituation of gill-withdrawal reflex in Aplysia californica. , 1982, Journal of neurophysiology.

[17]  E. Kandel The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[18]  P. Greengard,et al.  Synapsin I partially dissociates from synaptic vesicles during exocytosis induced by electrical stimulation , 1992, Neuron.

[19]  D. A. Baxter,et al.  Role of calcium-calmodulin-dependent protein kinase II in modulation of sensorimotor synapses in Aplysia. , 1997, Journal of neurophysiology.

[20]  Eric R Kandel,et al.  MAP Kinase Translocates into the Nucleus of the Presynaptic Cell and Is Required for Long-Term Facilitation in Aplysia , 1997, Neuron.

[21]  P. Greengard,et al.  Synapsin Controls Both Reserve and Releasable Synaptic Vesicle Pools during Neuronal Activity and Short-Term Plasticity inAplysia , 2001, The Journal of Neuroscience.

[22]  P. Greengard,et al.  Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation , 1983, The Journal of cell biology.

[23]  E. Kandel,et al.  Persistent and transcriptionally-dependent increase in protein phosphorylation in long-term facilitation ofAplysia sensory neurons , 1989, Nature.

[24]  F Benfenati,et al.  Synaptic vesicle phosphoproteins and regulation of synaptic function. , 1993, Science.

[25]  P. Greengard,et al.  Synapsins as mediators of BDNF-enhanced neurotransmitter release , 2000, Nature Neuroscience.

[26]  P. Greengard,et al.  Localization of synapsin I at the frog neuromuscular junction , 1988, Neuroscience.

[27]  P. Greengard,et al.  Regulation by synapsin I and Ca(2+)‐calmodulin‐dependent protein kinase II of the transmitter release in squid giant synapse. , 1991, The Journal of physiology.

[28]  Y. Goda,et al.  Actin-Dependent Regulation of Neurotransmitter Release at Central Synapses , 2000, Neuron.

[29]  P. De Camilli,et al.  Synapsins: mosaics of shared and individual domains in a family of synaptic vesicle phosphoproteins. , 1989, Science.

[30]  J. Byrne,et al.  TGF-beta1 in Aplysia: role in long-term changes in the excitability of sensory neurons and distribution of TbetaR-II-like immunoreactivity. , 1999, Learning & memory.

[31]  H. Crissman,et al.  Multiple kinase arrest points in the G1 phase of nontransformed mammalian cells are absent in transformed cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Homayouni,et al.  Dynamics of protein phosphorylation in sensory neurons of Aplysia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  S. Schacher,et al.  Synaptic plasticity in vitro: cell culture of identified Aplysia neurons mediating short-term habituation and sensitization , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[34]  T. Südhof The structure of the human synapsin I gene and protein. , 1990, The Journal of biological chemistry.

[35]  L. Brodin,et al.  Impairment of synaptic vesicle clustering and of synaptic transmission, and increased seizure propensity, in synapsin I-deficient mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R Llinás,et al.  Intraterminal injection of synapsin I or calcium/calmodulin-dependent protein kinase II alters neurotransmitter release at the squid giant synapse. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[37]  P. Greengard,et al.  The synapsins. , 1990, Annual review of cell biology.

[38]  P. Greengard,et al.  Synapsin I bundles F-actin in a phosphorylation-dependent manner , 1987, Nature.

[39]  P. Greengard,et al.  Synapsin dispersion and reclustering during synaptic activity , 2001, Nature Neuroscience.

[40]  E. Kandel,et al.  Synapse-Specific, Long-Term Facilitation of Aplysia Sensory to Motor Synapses: A Function for Local Protein Synthesis in Memory Storage , 1997, Cell.

[41]  R DeSalle,et al.  Molecular evolution of the synapsin gene family. , 1999, The Journal of experimental zoology.

[42]  T. Carew,et al.  Dynamics of Induction and Expression of Long-Term Synaptic Facilitation in Aplysia , 1996, The Journal of Neuroscience.

[43]  T. Südhof,et al.  Essential functions of synapsins I and II in synaptic vesicle regulation , 1995, Nature.

[44]  H Taniguchi,et al.  Site-specific Phosphorylation of Synapsin I by Mitogen-activated Protein Kinase and Cdk5 and Its Effects on Physiological Functions* , 1996, The Journal of Biological Chemistry.

[45]  J. Byrne,et al.  Identification of two phosphoproteins affected by serotonin in Aplysia sensory neurons , 1997, Brain Research.

[46]  Thomas C. Südhof,et al.  Short-term synaptic plasticity is altered in mice lacking synapsin I , 1993, Cell.

[47]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[48]  P. Greengard,et al.  Characterization of synapsin I binding to small synaptic vesicles. , 1986, The Journal of biological chemistry.

[49]  T. Godenschwege,et al.  Invertebrate Synapsins: A Single Gene Codes for Several Isoforms in Drosophila , 1996, The Journal of Neuroscience.

[50]  J. Byrne,et al.  Transforming Growth Factor β1 Alters Synapsin Distribution and Modulates Synaptic Depression inAplysia , 2002, The Journal of Neuroscience.

[51]  M. Klein Synaptic augmentation by 5-HT at rested aplysia sensorimotor synapses: Independence of action potential prolongation , 1994, Neuron.

[52]  T. Südhof,et al.  A Phospho-Switch Controls the Dynamic Association of Synapsins with Synaptic Vesicles , 1999, Neuron.

[53]  E R Kandel,et al.  Presynaptic facilitation revisited: state and time dependence , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[54]  E. Kandel,et al.  Pairing-specific, activity-dependent presynaptic facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.