GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing–Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus

Abstract The dorsal raphe nucleus (DRn) receives glutamatergic inputs from numerous brain areas that control the function of DRn serotonin (5-HT) neurons. By integrating these synaptic inputs, 5-HT neurons modulate a plethora of behaviors and physiological functions. However, it remains unknown whether the excitatory inputs onto DRn 5-HT neurons can undergo activity-dependent change of strength, as well as the mechanisms that control their plasticity. Here, we describe a novel form of spike-timing–dependent long-term potentiation (tLTP) of glutamate synapses onto rat DRn 5-HT neurons. This form of synaptic plasticity is initiated by an increase in postsynaptic intracellular calcium but is maintained by a persistent increase in the probability of glutamate release. The tLTP of glutamate synapses onto DRn 5-HT is independent of NMDA receptors but requires the activation of calcium-permeable AMPA receptors and voltage-dependent calcium channels. The presynaptic expression of the tLTP is mediated by the retrograde messenger nitric oxide (NO) and activation of cGMP/PKG pathways. Collectively, these results indicate that glutamate synapses in the DRn undergo activity-dependent synaptic plasticity gated by NO signaling and unravel a previously unsuspected role of NO in controlling synaptic function and plasticity in the DRn.

[1]  S. Vincent,et al.  Molecular Characterization of a Type II Cyclic GMP‐Dependent Protein Kinase Expressed in the Rat Brain , 1995, Journal of neurochemistry.

[2]  B. Waterhouse,et al.  Glutamatergic afferent projections to the dorsal raphe nucleus of the rat , 2003, Brain Research.

[3]  K. Fox,et al.  The role of nitric oxide in pre-synaptic plasticity and homeostasis , 2013, Front. Cell. Neurosci..

[4]  C. Rampon,et al.  Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods , 1997, Neuroscience.

[5]  L. Abbott,et al.  Competitive Hebbian learning through spike-timing-dependent synaptic plasticity , 2000, Nature Neuroscience.

[6]  J. Roder,et al.  Enhanced LTP in Mice Deficient in the AMPA Receptor GluR2 , 1996, Neuron.

[7]  D. Monti,et al.  Role of nitric oxide in sleep regulation: effects of l-NAME, an inhibitor of nitric oxide synthase, on sleep in rats , 1999, Behavioural Brain Research.

[8]  T. Robbins,et al.  Serotoninergic regulation of emotional and behavioural control processes , 2008, Trends in Cognitive Sciences.

[9]  P. Currie,et al.  Anorexigenic action of nitric oxide synthase inhibition in the raphe nuclei , 2011, Neuroreport.

[10]  H. Pape,et al.  Heterosynaptic long‐term potentiation at interneuron–principal neuron synapses in the amygdala requires nitric oxide signalling , 2012, The Journal of physiology.

[11]  P. Somogyi,et al.  Calcium-Permeable AMPA Receptors Provide a Common Mechanism for LTP in Glutamatergic Synapses of Distinct Hippocampal Interneuron Types , 2012, The Journal of Neuroscience.

[12]  N. Pivac,et al.  The role of the serotonergic system at the interface of aggression and suicide , 2013, Neuroscience.

[13]  S. Haj-Dahmane,et al.  Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus , 2014, The Journal of Neuroscience.

[14]  B. Jacobs,et al.  Serotonin and motor activity , 1997, Current Opinion in Neurobiology.

[15]  G. Barrionuevo,et al.  Bidirectional Hebbian Plasticity at Hippocampal Mossy Fiber Synapses on CA3 Interneurons , 2008, The Journal of Neuroscience.

[16]  S. Maier,et al.  Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus , 2000, Behavioural Brain Research.

[17]  D. Feldman.  The Spike-Timing Dependence of Plasticity , 2012, Neuron.

[18]  S. Haj-Dahmane,et al.  Endocannabinoids Suppress Excitatory Synaptic Transmission to Dorsal Raphe Serotonin Neurons through the Activation of Presynaptic CB1 Receptors , 2009, Journal of Pharmacology and Experimental Therapeutics.

[19]  N. Daw,et al.  Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex. , 2003, Cerebral cortex.

[20]  Olivier Camiré,et al.  Dendritic Calcium Nonlinearities Switch the Direction of Synaptic Plasticity in Fast-Spiking Interneurons , 2014, The Journal of Neuroscience.

[21]  H. Fink,et al.  Serotonin controlling feeding and satiety , 2015, Behavioural Brain Research.

[22]  H. Takagi,et al.  Maturation of a PKG-Dependent Retrograde Mechanism for Exoendocytic Coupling of Synaptic Vesicles , 2012, Neuron.

[23]  K. Fuxe,et al.  Localization of monoamines in the lower brain stem , 1964, Experientia.

[24]  G. Silberberg,et al.  A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei , 2014, Neuron.

[25]  J. Garthwaite,et al.  Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase , 1995, Neuroscience.

[26]  J. Kauer,et al.  PKG and PKA Signaling in LTP at GABAergic Synapses , 2009, Neuropsychopharmacology.

[27]  Jeremiah Y. Cohen,et al.  Serotonergic neurons signal reward and punishment on multiple timescales , 2015, eLife.

[28]  J. Simon Wiegert,et al.  AMPA receptors gate spine Ca2+ transients and spike-timing-dependent potentiation , 2010, Proceedings of the National Academy of Sciences.

[29]  A. Beaudet,et al.  The serotonin neurons in nucleus raphe dorsalis of adult rat: A light and electron microscope radioautographic study , 1982, The Journal of comparative neurology.

[30]  S. Haj-Dahmane.  D2‐like dopamine receptor activation excites rat dorsal raphe 5‐HT neurons in vitro , 2001, The European journal of neuroscience.

[31]  B. Waterhouse,et al.  Retrograde double‐labeling study of common afferent projections to the dorsal raphe and the nuclear core of the locus coeruleus in the rat , 2005, The Journal of comparative neurology.

[32]  S. Haj-Dahmane,et al.  The Wake-Promoting Peptide Orexin-B Inhibits Glutamatergic Transmission to Dorsal Raphe Nucleus Serotonin Neurons through Retrograde Endocannabinoid Signaling , 2005, The Journal of Neuroscience.

[33]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[34]  G. Aghajanian,et al.  The role of serotonin in the pathophysiology and treatment of schizophrenia. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[35]  B. Jacobs,et al.  Activity of brain serotonergic neurons in the behaving animal. , 1991, Pharmacological reviews.

[36]  H. Schulman,et al.  Nitric Oxide Modulates Synaptic Vesicle Docking/Fusion Reactions , 1996, Neuron.

[37]  E. Kandel,et al.  Role of guanylyl cyclase and cGMP-dependent protein kinase in long-term potentiation , 1994, Nature.

[38]  Liqun Luo,et al.  Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons , 2014, Neuron.

[39]  Jean-Claude Béïque,et al.  Target-specific modulation of the descending prefrontal cortex inputs to the dorsal raphe nucleus by cannabinoids , 2016, Proceedings of the National Academy of Sciences.

[40]  G. Aghajanian,et al.  Neurokinins Activate Local Glutamatergic Inputs to Serotonergic Neurons of the Dorsal Raphe Nucleus , 2002, Neuropsychopharmacology.

[41]  C. Hölscher.  Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity , 1997, Trends in Neurosciences.

[42]  R. Pobbe,et al.  Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter , 2010, Behavioural Brain Research.

[43]  J. Corbin,et al.  cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action , 2010, Pharmacological Reviews.

[44]  E. Kandel,et al.  Activity-dependent long-term enhancement of transmitter release by presynaptic 3′,5′-cyclic GMP in cultured hippocampal neurons , 1995, Nature.

[45]  S. Maier,et al.  Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor , 1999, Brain Research.

[46]  Richard L. Huganir,et al.  AMPARs and Synaptic Plasticity: The Last 25 Years , 2013, Neuron.

[47]  T. Hökfelt,et al.  Expression of galanin and nitric oxide synthase in subpopulations of serotonin neurons of the rat dorsal raphe nucleus , 1997, Journal of Chemical Neuroanatomy.

[48]  J. Garthwaite,et al.  Nitric Oxide Is Required for L-Type Ca2+ Channel-Dependent Long-Term Potentiation in the Hippocampus , 2016, Front. Synaptic Neurosci..

[49]  Carson C. Chow,et al.  Calcium time course as a signal for spike-timing-dependent plasticity. , 2005, Journal of neurophysiology.

[50]  Brian J. Wiltgen,et al.  A Role for Calcium-Permeable AMPA Receptors in Synaptic Plasticity and Learning , 2010, PloS one.

[51]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[52]  R. Malenka,et al.  AMPA receptor trafficking and synaptic plasticity. , 2002, Annual review of neuroscience.

[53]  D. Bredt,et al.  Synaptic signaling by nitric oxide , 1997, Current Opinion in Neurobiology.

[54]  T. L. Krukoff,et al.  Stress‐induced activation of nitric oxide‐producing neurons in the rat brain , 1997, The Journal of comparative neurology.

[55]  Kae Nakamura,et al.  Functions and computational principles of serotonergic and related systems at multiple scales , 2014, Front. Integr. Neurosci..

[56]  P. Dayan,et al.  Serotonin's many meanings elude simple theories , 2015, eLife.

[57]  S. Ikemoto,et al.  The midbrain raphe nuclei mediate primary reinforcement via GABAA receptors , 2007, The European journal of neuroscience.

[58]  D. Bredt,et al.  Interaction of Nitric Oxide Synthase with the Postsynaptic Density Protein PSD-95 and α1-Syntrophin Mediated by PDZ Domains , 1996, Cell.

[59]  J. Monti,et al.  Serotonin control of sleep-wake behavior. , 2011, Sleep medicine reviews.

[60]  B. Waterhouse,et al.  Differential expression of nitric oxide in serotonergic projection neurons: Neurochemical identification of dorsal raphe inputs to rodent trigeminal somatosensory targets , 2003, The Journal of comparative neurology.

[61]  J. Deniau,et al.  Asymmetric spike-timing dependent plasticity of striatal nitric oxide-synthase interneurons , 2009, Neuroscience.

[62]  Kae Nakamura,et al.  Reward-Dependent Modulation of Neuronal Activity in the Primate Dorsal Raphe Nucleus , 2008, The Journal of Neuroscience.

[63]  F. Guimarães,et al.  Nitric oxide-mediated anxiolytic-like and antidepressant-like effects in animal models of anxiety and depression , 2008, Pharmacology Biochemistry and Behavior.

[64]  M. Bartos,et al.  Joint CP-AMPA and group I mGlu receptor activation is required for synaptic plasticity in dentate gyrus fast-spiking interneurons , 2014, Proceedings of the National Academy of Sciences.

[65]  S. Haj-Dahmane,et al.  Time-dependent modulation of glutamate synapses onto 5-HT neurons by antidepressant treatment , 2015, Neuropharmacology.

[66]  Minmin Luo,et al.  Dorsal Raphe Neurons Signal Reward through 5-HT and Glutamate , 2014, Neuron.

[67]  L. Wiklund,et al.  Possible excitatory amino acid afferents to nucleus raphe dorsalis of the rat investigated with retrograde wheat germ agglutinin and d-[3H]aspartate tracing , 1985, Brain Research.

[68]  B. Waterhouse,et al.  Acute restraint increases NADPH-diaphorase staining in distinct subregions of the rat dorsal raphe nucleus: Implications for raphe serotonergic and nitrergic transmission , 2006, Brain Research.

[69]  J. Garthwaite.  From synaptically localized to volume transmission by nitric oxide , 2016, The Journal of physiology.

[70]  T. Mittmann,et al.  Presynaptic nitric oxide/cGMP facilitates glutamate release via hyperpolarization‐activated cyclic nucleotide‐gated channels in the hippocampus , 2011, The European journal of neuroscience.

[71]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[72]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[73]  M. Poo,et al.  Spike Timing-Dependent LTP/LTD Mediates Visual Experience-Dependent Plasticity in a Developing Retinotectal System , 2006, Neuron.

[74]  S. T. Kitai,et al.  The organization of divergent axonal projections from the midbrain raphe nuclei in the rat , 1986, The Journal of comparative neurology.