title: Nitric oxide is an activity-dependent regulator of target neuron intrinsic excitability.
abstract: Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours.
authors.affiliation: Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, Hodgkin Building, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.forename: Susan W
authors.initials: SW
authors.lastname: Robinson
authors.forename: Huaxia
authors.initials: H
authors.lastname: Tong
authors.forename: Martin D
authors.initials: MD
authors.lastname: Haustein
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kopp-Scheinpflug
authors.forename: Ian D
authors.initials: ID
authors.lastname: Forsythe
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D001933:Brain Stem / Q000166:cytology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051669:Shab Potassium Channels / Q000172:deficiency / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006834:Hydrazines; D007211:Indoles; D020030:Nitric Oxide Donors; C112653:PAPA NONOate; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D051669:Shab Potassium Channels; D051670:Shaw Potassium Channels; D009599:Nitroprusside; D009569:Nitric Oxide; D018698:Glutamic Acid; D019789:Tetraethylammonium; C064758:Ro 31-8220