title: Neuronal nitric oxide contributes to neuroplasticity-associated protein expression through cGMP, protein kinase G, and extracellular signal-regulated kinase.
abstract: Nitric oxide (NO) synthesized by neuronal NO synthase (nNOS) has long been implicated in brain plasticity. However, it is unclear how this short-lived mediator contributes to the long-term molecular changes underlying neuroplasticity, which typically require activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathway and gene expression. To address this issue, we used a neuroplasticity model based on treatment of neuronal cultures with bicuculline and a model of experience-dependent plasticity in the barrel cortex. In neuronal cultures, NOS inhibition attenuated the bicuculline-induced activation of ERK and the expression of c-Fos, Egr-1, Arc, and brain-derived neurotrophic factor (BDNF), proteins essential for neuroplasticity. Furthermore, inhibition of the NO target soluble guanylyl cyclase or of the cGMP effector kinase protein kinase G (PKG) reduced both ERK activation and plasticity-related protein expression. NOS inhibition did not affect phosphorylation of cAMP response element-binding protein (CREB), a well-established ERK nuclear target, but it attenuated the nuclear accumulation of the CREB coactivator TORC1 and suppressed the activation of Elk-1, another transcription factor target of ERK. Consistent with these in vitro observations, induction of c-Fos, Egr-1, and BDNF was attenuated in the D1 cortical barrel of nNOS(-/-) mice subjected to single whisker experience. These results establish nNOS-derived NO as a key factor in the expression of proteins involved in neuroplasticity, an effect mediated through cGMP, PKG, and ERK signaling. These actions of NO do not depend on CREB phosphorylation but may involve TORC1 and Elk-1. Our data unveil a previously unrecognized link between neuronal NO and the molecular machinery responsible for the sustained synaptic changes underlying neuroplasticity.
authors.affiliation: Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Gallo
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013003:Somatosensory Cortex / Q000187:drug effects / Q000502:physiology; D014738:Vibrissae / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C092069:activity regulated cytoskeletal-associated protein; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D006152:Cyclic GMP; D001640:Bicuculline