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• W2004694849 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. 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. Synaptic input drives NO-mediated modulation of voltage-gated potassium currents High synaptic activity switches the dominant delayed rectifier to Kv2 NO volume transmission tunes target neurons to excitatory synaptic drive This homeostatic regulation occurs broadly in the brain (brain stem and hippocampus) A multitude of control mechanisms act to tune ion channel activity to neuronal function and network activity, thereby refining synaptic integration and the computation encoded in the action potential (AP) output (Marder and Goaillard, 2006Marder E. Goaillard J.M. Variability, compensation and homeostasis in neuron and network function.Nat. Rev. Neurosci. 2006; 7: 563-574Crossref PubMed Scopus (802) Google Scholar, Nelson and Turrigiano, 2008Nelson S.B. Turrigiano G.G. Strength through diversity.Neuron. 2008; 60: 477-482Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). Activity-dependent processes are clearly associated with synaptic scaling and long-term changes in synaptic strength that enhance or suppress the ability of particular synaptic inputs to trigger postsynaptic APs, with many of these mechanisms (such as LTP and LTD) underlying learning and memory (Morris et al., 2003Morris R.G. Moser E.I. Riedel G. Martin S.J. Sandin J. Day M. O'Carroll C. Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 773-786Crossref PubMed Scopus (394) Google Scholar). Many studies show changes in synaptic strength, but synaptic activity can also regulate voltage-gated conductances (Frick et al., 2004Frick A. Magee J. Johnston D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.Nat. Neurosci. 2004; 7: 126-135Crossref PubMed Scopus (357) Google Scholar). We postulate that nitrergic signaling links synaptic activity to the control of postsynaptic intrinsic excitability in many areas of the brain, including the hippocampus (Frick et al., 2004Frick A. Magee J. Johnston D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.Nat. Neurosci. 2004; 7: 126-135Crossref PubMed Scopus (357) Google Scholar, Misonou et al., 2004Misonou H. Mohapatra D.P. Park E.W. Leung V. Zhen D. Misonou K. Anderson A.E. Trimmer J.S. Regulation of ion channel localization and phosphorylation by neuronal activity.Nat. Neurosci. 2004; 7: 711-718Crossref PubMed Scopus (351) Google Scholar, Mohapatra et al., 2009Mohapatra D.P. Misonou H. Pan S.J. Held J.E. Surmeier D.J. Trimmer J.S. Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the KV2.1 potassium channel.Channels (Austin). 2009; 3: 46-56Crossref PubMed Scopus (73) Google Scholar, van Welie et al., 2006van Welie I. van Hooft J.A. Wadman W.J. Background activity regulates excitability of rat hippocampal CA1 pyramidal neurons by adaptation of a K+ conductance.J. Neurophysiol. 2006; 95: 2007-2012Crossref PubMed Scopus (18) Google Scholar) and auditory brain stem (Song et al., 2005Song P. Yang Y. Barnes-Davies M. Bhattacharjee A. Hamann M. Forsythe I.D. Oliver D.L. Kaczmarek L.K. Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons.Nat. Neurosci. 2005; 8: 1335-1342Crossref PubMed Scopus (109) Google Scholar, Steinert et al., 2008Steinert J.R. Kopp-Scheinpflug C. Baker C. Challiss R.A. Mistry R. Haustein M.D. Griffin S.J. Tong H. Graham B.P. Forsythe I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.Neuron. 2008; 60: 642-656Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). Neuronal excitability is determined by the expression, location, and activity of voltage-gated ion channels in the plasma membrane. Na+ and Ca2+ channels dominate AP generation, but the crucial regulators of excitability are voltage-gated potassium (K+) channels. There are over 40 α subunit K+ channel genes (Coetzee et al., 1999Coetzee W.A. Amarillo Y. Chiu J. Chow A. Lau D. McCormack T. Moreno H. Nadal M.S. Ozaita A. Pountney D. et al.Molecular diversity of K+ channels.Ann. N Y Acad. Sci. 1999; 868: 233-285Crossref PubMed Scopus (986) Google Scholar, Gutman et al., 2003Gutman G.A. Chandy K.G. Adelman J.P. Aiyar J. Bayliss D.A. Clapham D.E. Covarriubias M. Desir G.V. Furuichi K. Ganetzky B. et al.International Union of PharmacologyInternational Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels.Pharmacol. Rev. 2003; 55: 583-586Crossref PubMed Scopus (259) Google Scholar) associated with 12 families (Kv1–12). A native channel requires four α subunits (usually from within the same family) with heterogeneity providing a spectrum of channel kinetics. They set resting membrane potentials, neuronal excitability, AP waveform, firing threshold, and firing rates. Here, we focus on two broadly expressed families: Kv2 (Du et al., 2000Du J. Haak L.L. Phillips-Tansey E. Russell J.T. McBain C.J. Frequency-dependent regulation of rat hippocampal somato-dendritic excitability by the K+ channel subunit Kv2.1.J. Physiol. 2000; 522: 19-31Crossref PubMed Scopus (165) Google Scholar, Guan et al., 2007Guan D. Tkatch T. Surmeier D.J. Armstrong W.E. Foehring R.C. Kv2 subunits underlie slowly inactivating potassium current in rat neocortical pyramidal neurons.J. Physiol. 2007; 581: 941-960Crossref PubMed Scopus (82) Google Scholar, Johnston et al., 2008Johnston J. Griffin S.J. Baker C. Skrzypiec A. Chernova T. Forsythe I.D. Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons.J. Physiol. 2008; 586: 3493-3509Crossref PubMed Scopus (93) Google Scholar), and Kv3 (Rudy et al., 1999Rudy B. Chow A. Lau D. Amarillo Y. Ozaita A. Saganich M. Moreno H. Nadal M.S. Hernandez-Pineda R. Hernandez-Cruz A. et al.Contributions of Kv3 channels to neuronal excitability.Ann. N Y Acad. Sci. 1999; 868: 304-343Crossref PubMed Scopus (260) Google Scholar, Rudy and McBain, 2001Rudy B. McBain C.J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.Trends Neurosci. 2001; 24: 517-526Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar, Wang et al., 1998Wang L.Y. Gan L. Forsythe I.D. Kaczmarek L.K. Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones.J. Physiol. 1998; 509: 183-194Crossref PubMed Scopus (291) Google Scholar), which are well characterized and underlie many neuronal “delayed rectifiers” (Hodgkin and Huxley, 1952Hodgkin A.L. Huxley A.F. A quantitative description of membrane current and its application to conduction and excitation in nerve.J. Physiol. 1952; 117: 500-544Crossref PubMed Scopus (14532) Google Scholar) throughout the nervous system. Both Kv2 and Kv3 are “high voltage-activated channels (HVAs),” requiring depolarization to the relatively positive voltages achieved during an AP, with half-activation voltages around 0 mV (±20 mV, dependent on subunit composition, accessory subunits, and phosphorylation). Kv2 channels have a broader activation range and slower kinetics than Kv3, so that Kv2 starts to activate close to AP threshold and is slower to deactivate (and slower to inactivate). The subcellular localization of Kv2 and Kv3 channels differs substantially; Kv2 channels are often clustered or “corralled” (Misonou et al., 2004Misonou H. Mohapatra D.P. Park E.W. Leung V. Zhen D. Misonou K. Anderson A.E. Trimmer J.S. Regulation of ion channel localization and phosphorylation by neuronal activity.Nat. Neurosci. 2004; 7: 711-718Crossref PubMed Scopus (351) Google Scholar, Muennich and Fyffe, 2004Muennich E.A. Fyffe R.E. Focal aggregation of voltage-gated, Kv2.1 subunit-containing, potassium channels at synaptic sites in rat spinal motoneurones.J. Physiol. 2004; 554: 673-685Crossref PubMed Scopus (99) Google Scholar, O'Connell et al., 2006O'Connell K.M. Rolig A.S. Whitesell J.D. Tamkun M.M. Kv2.1 potassium channels are retained within dynamic cell surface microdomains that are defined by a perimeter fence.J. Neurosci. 2006; 26: 9609-9618Crossref PubMed Scopus (108) Google Scholar) and are localized to axon initial segments (AISs) (Johnston et al., 2008Johnston J. Griffin S.J. Baker C. Skrzypiec A. Chernova T. Forsythe I.D. Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons.J. Physiol. 2008; 586: 3493-3509Crossref PubMed Scopus (93) Google Scholar, Sarmiere et al., 2008Sarmiere P.D. Weigle C.M. Tamkun M.M. The Kv2.1 K+ channel targets to the axon initial segment of hippocampal and cortical neurons in culture and in situ.BMC Neurosci. 2008; 9: 112Crossref PubMed Scopus (66) Google Scholar) or proximal dendrites. Kv3.1 channels can be found in postsynaptic soma and AIS and are sometimes located at nodes of Ranvier (Devaux et al., 2003Devaux J. Alcaraz G. Grinspan J. Bennett V. Joho R. Crest M. Scherer S.S. Kv3.1b is a novel component of CNS nodes.J. Neurosci. 2003; 23: 4509-4518Crossref PubMed Google Scholar) and on the nonrelease face of excitatory synapses (Elezgarai et al., 2003Elezgarai I. Díez J. Puente N. Azkue J.J. Benítez R. Bilbao A. Knöpfel T. Doñate-Oliver F. Grandes P. Subcellular localization of the voltage-dependent potassium channel Kv3.1b in postnatal and adult rat medial nucleus of the trapezoid body.Neuroscience. 2003; 118: 889-898Crossref PubMed Scopus (50) Google Scholar). Distinction between native Kv3 and Kv2 channels is best based on their pharmacology: Kv3 channels are blocked by low concentrations (1 mM) of tetraethylammonium (TEA) (Grissmer et al., 1994Grissmer S. Nguyen A.N. Aiyar J. Hanson D.C. Mather R.J. Gutman G.A. Karmilowicz M.J. Auperin D.D. Chandy K.G. Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines.Mol. Pharmacol. 1994; 45: 1227-1234PubMed Google Scholar, Wang et al., 1998Wang L.Y. Gan L. Forsythe I.D. Kaczmarek L.K. Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones.J. Physiol. 1998; 509: 183-194Crossref PubMed Scopus (291) Google Scholar), whereas Kv2 channel gating is shifted to more positive voltages by r-stromatoxin-1 (Escoubas et al., 2002Escoubas P. Diochot S. Célérier M.L. Nakajima T. Lazdunski M. Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies.Mol. Pharmacol. 2002; 62: 48-57Crossref PubMed Scopus (150) Google Scholar). Most neuronal Kv2 channels contain Kv2.1 subunits, as in the hippocampus (Du et al., 2000Du J. Haak L.L. Phillips-Tansey E. Russell J.T. McBain C.J. Frequency-dependent regulation of rat hippocampal somato-dendritic excitability by the K+ channel subunit Kv2.1.J. Physiol. 2000; 522: 19-31Crossref PubMed Scopus (165) Google Scholar), whereas Kv2.2 has a more restricted expression, such as the medial nucleus of the trapezoid body (MNTB) (Johnston et al., 2008Johnston J. Griffin S.J. Baker C. Skrzypiec A. Chernova T. Forsythe I.D. Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons.J. Physiol. 2008; 586: 3493-3509Crossref PubMed Scopus (93) Google Scholar). Neuronal nitric oxide synthase (nNOS) is widely expressed in the brain, activated by Ca2+ influx through synaptic NMDARs (Brenman et al., 1996Brenman J.E. Chao D.S. Gee S.H. McGee A.W. Craven S.E. Santillano D.R. Wu Z. Huang F. Xia H. Peters M.F. et al.Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains.Cell. 1996; 84: 757-767Abstract Full Text Full Text PDF PubMed Scopus (1446) Google Scholar, Garthwaite et al., 1988Garthwaite J. Charles S.L. Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain.Nature. 1988; 336: 385-388Crossref PubMed Scopus (2284) Google Scholar) and linked with synaptic plasticity in the cerebellum (Boxall and Garthwaite, 1996Boxall A.R. Garthwaite J. Long-term depression in rat cerebellum requires both NO synthase and NO-sensitive guanylyl cyclase.Eur. J. Neurosci. 1996; 8: 2209-2212Crossref PubMed Scopus (83) Google Scholar, Shin and Linden, 2005Shin J.H. Linden D.J. An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal.J. Neurophysiol. 2005; 94: 4281-4289Crossref PubMed Scopus (99) Google Scholar), hippocampus (Lu et al., 1999Lu Y.F. Kandel E.R. Hawkins R.D. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus.J. Neurosci. 1999; 19: 10250-10261Crossref PubMed Google Scholar), and neocortex (Hardingham and Fox, 2006Hardingham N. Fox K. The role of nitric oxide and GluR1 in presynaptic and postsynaptic components of neocortical potentiation.J. Neurosci. 2006; 26: 7395-7404Crossref PubMed Scopus (88) Google Scholar). Nitric oxide (NO) is associated with signaling across many physiological systems, including cardiovascular, immune, and enteric and central nervous systems, and related to disease and pathological states (Garthwaite, 2008Garthwaite J. Concepts of neural nitric oxide-mediated transmission.Eur. J. Neurosci. 2008; 27: 2783-2802Crossref PubMed Scopus (649) Google Scholar, Steinert et al., 2010aSteinert J.R. Chernova T. Forsythe I.D. Nitric oxide signaling in brain function, dysfunction, and dementia.Neuroscientist. 2010; 16: 435-452Crossref PubMed Scopus (369) Google Scholar). nNOS is often localized to subpopulations of neurons in a given region, and the source or the specific targets of nitrergic signaling are hard to identify at a molecular level or in a physiological context. Soluble guanylyl cyclase (sGC) is the major NO receptor and hence, cGMP-mediated activation of PKG and subsequent changes in the balance of kinase/phosphatase activity modulates target protein phosphorylation, such as ligand- (Serulle et al., 2007Serulle Y. Zhang S. Ninan I. Puzzo D. McCarthy M. Khatri L. Arancio O. Ziff E.B. A GluR1-cGKII interaction regulates AMPA receptor trafficking.Neuron. 2007; 56: 670-688Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar) and voltage-gated ion channels (Park et al., 2006Park K.S. Mohapatra D.P. Misonou H. Trimmer J.S. Graded regulation of the Kv2.1 potassium channel by variable phosphorylation.Science. 2006; 313: 976-979Crossref PubMed Scopus (230) Google Scholar). Recent evidence from the auditory brain stem demonstrates that Kv3.1 channels are a target for cGMP/NO-signaling pathways following synaptic activity (Steinert et al., 2008Steinert J.R. Kopp-Scheinpflug C. Baker C. Challiss R.A. Mistry R. Haustein M.D. Griffin S.J. Tong H. Graham B.P. Forsythe I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.Neuron. 2008; 60: 642-656Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). NO is also postulated to act as a retrograde transmitter, and although presynaptic actions are known (Garthwaite, 2008Garthwaite J. Concepts of neural nitric oxide-mediated transmission.Eur. J. Neurosci. 2008; 27: 2783-2802Crossref PubMed Scopus (649) Google Scholar), i.e., through volume transmission (Artinian et al., 2010Artinian L. Tornieri K. Zhong L. Baro D. Rehder V. Nitric oxide acts as a volume transmitter to modulate electrical properties of spontaneously firing neurons via apamin-sensitive potassium channels.J. Neurosci. 2010; 30: 1699-1711Crossref PubMed Scopus (22) Google Scholar, Steinert et al., 2008Steinert J.R. Kopp-Scheinpflug C. Baker C. Challiss R.A. Mistry R. Haustein M.D. Griffin S.J. Tong H. Graham B.P. Forsythe I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.Neuron. 2008; 60: 642-656Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar), the present study focuses on signaling to postsynaptic targets. Expression of Kv3 and Kv2 channels in association with NO and glutamatergic signaling occurs broadly in the brain, including the auditory brain stem (Johnston et al., 2008Johnston J. Griffin S.J. Baker C. Skrzypiec A. Chernova T. Forsythe I.D. Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons.J. Physiol. 2008; 586: 3493-3509Crossref PubMed Scopus (93) Google Scholar, Steinert et al., 2008Steinert J.R. Kopp-Scheinpflug C. Baker C. Challiss R.A. Mistry R. Haustein M.D. Griffin S.J. Tong H. Graham B.P. Forsythe I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.Neuron. 2008; 60: 642-656Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar) and hippocampus (Tansey et al., 2002Tansey E.P. Chow A. Rudy B. McBain C.J. Developmental expression of potassium-channel subunit Kv3.2 within subpopulations of mouse hippocampal inhibitory interneurons.Hippocampus. 2002; 12: 137-148Crossref PubMed Scopus (60) Google Scholar). In this study nitrergic signaling was activated by sustained excitatory synaptic activity (10 Hz) for around 1 hr, modulating excitability of principal neurons in the MNTB and CA3 pyramidal neurons by suppression of Kv3 conductances and dramatic enhancement of Kv2 currents. This switched the drive for AP repolarization to Kv2 channels, raising firing threshold and altering AP responses in both brain regions. The nitrergic facilitation of Kv2 implies that this conductance is more dominant in vivo than previously suspected because recording within minutes of animal sacrifice shows vastly enhanced Kv2 currents. Throughout this study, we used whole-cell patch recording in an unpaired fashion: control data were recorded from one population of neurons, then conditioning stimulation was applied to the synaptic pathways, followed by test recordings from another population of neurons; this avoided dialysis inherent in long-term recording from the same neuron. The objective was to test if sustained excitatory synaptic input to a target neuron changed its intrinsic excitability. This is distinct from short-term depression of synaptic responses observed following short periods of conditioning spontaneous activity (Hennig et al., 2008Hennig M.H. Postlethwaite M. Forsythe I.D. Graham B.P. Interactions between multiple sources of short-term plasticity during evoked and spontaneous activity at the rat calyx of Held.J. Physiol. 2008; 586: 3129-3146Crossref PubMed Scopus (20) Google Scholar, Hermann et al., 2007Hermann J. Pecka M. von Gersdorff H. Grothe B. Klug A. Synaptic transmission at the calyx of Held under in vivo like activity levels.J. Neurophysiol. 2007; 98: 807-820Crossref PubMed Scopus (115) Google Scholar) in that our studies focused on how sustained synaptic inputs can influence postsynaptic voltage-gated conductances rather than synaptic strength. The conditioning synaptic stimulation lasted 1 hr and consisted of evoked EPSPs at a mean frequency of 10 Hz (with interstimulus intervals [ISIs] generated by a Poisson process, giving a total of 34,875 stimuli/1 hr). We stimulated the trapezoid body calyceal projection to the MNTB or mossy fiber/commissural projections (which were DCG-IV insensitive; see Figure S1C available online) to CA3 pyramidal neurons. Stimulation at 10 Hz induces neither LTP nor LTD (Dudek and Bear, 1992Dudek S.M. Bear M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.Proc. Natl. Acad. Sci. USA. 1992; 89: 4363-4367Crossref PubMed Scopus (1324) Google Scholar) and provided a sustainable stimulation rate that did not deplete transmission to subthreshold levels (Figure S1A, stimulus recordings at 55 min) and was comparable with physiological firing rates for the MNTB (Kopp-Scheinpflug et al., 2003Kopp-Scheinpflug C. Lippe W.R. Dörrscheidt G.J. Rübsamen R. The medial nucleus of the trapezoid body in the gerbil is more than a relay: comparison of pre- and postsynaptic activity.J. Assoc. Res. Otolaryngol. 2003; 4: 1-23Crossref PubMed Scopus (103) Google Scholar) and hippocampus (Fenton and Muller, 1998Fenton A.A. Muller R.U. Place cell discharge is extremely variable during individual passes of the rat through the firing field.Proc. Natl. Acad. Sci. USA. 1998; 95: 3182-3187Crossref PubMed Scopus (194) Google Scholar, Klyachko and Stevens, 2006Klyachko V.A. Stevens C.F. Excitatory and feed-forward inhibitory hippocampal synapses work synergistically as an adaptive filter of natural spike trains.PLoS Biol. 2006; 4: e207Crossref PubMed Scopus (123) Google Scholar). In naive slices under current clamp recording, evoked EPSP trains at moderate frequencies securely triggered APs in principal neurons of the MNTB (<400 Hz). The illustrated example in Figure 1 shows single AP responses to each presynaptic stimulus at a frequency of 100 Hz (Figure 1A, Naive, upper black). But transmission failure occurred rapidly at 800 Hz or above (Figure 1A, Naive, lower black), consistent with previous reports (Taschenberger and von Gersdorff, 2000Taschenberger H. von Gersdorff H. Fine-tuning an auditory synapse for speed and fidelity: developmental changes in presynaptic waveform, EPSC kinetics, and synaptic plasticity.J. Neurosci. 2000; 20: 9162-9173Crossref PubMed Google Scholar). After synaptic conditioning (post-conditioning, PC: 1 hr stimuli), the response of MNTB neurons to moderate frequency stimuli was robust and unchanged (Figure 1A, upper red trace; 100 Hz, PC), but high-frequency stimuli now triggered APs with greater reliability (Figure 1A, PC, lower red trace; 800 Hz). The conditioning reduced evoked synaptic currents (Figure S1B), consistent with nitrergic suppression of AMPARs reported previously (Steinert et al., 2008Steinert J.R. Kopp-Scheinpflug C. Baker C. Challiss R.A. Mistry R. Haustein M.D. Griffin S.J. Tong H. Graham B.P. Forsythe I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.Neuron. 2008; 60: 642-656Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar). Comparison of the mean output (MNTB APs) to input (at 100, 800, or 1000 Hz) for naive (Figure 1B, black bars) and PC slices (red bars) showed increased reliability of transmission for high-frequency stimulation after conditioning. The synaptic conditioning also increased AP threshold (Figure 1C), consistent with reduced postsynaptic excitability. AMPAR and NMDAR antagonists (50 μM AP-5, 10 μM MK801, 10 μM CNQX applied for the 1 hr conditioning period) blocked these changes, whereas perfusion of NO donors (NO: sodium nitroprusside, SNP or PapaNONOate, each 100 μM for 1 hr) mimicked the threshold increase (Figure 1D). Analogous changes in excitability also occurred in the hippocampus, where naive CA3 pyramidal neurons (CA3 neurons) responded with AP bursts to stimulation of the mossy fiber/commissural synaptic inputs (Brown and Randall, 2009Brown J.T. Randall A.D. Activity-dependent depression of the spike after-depolarization generates long-lasting intrinsic plasticity in hippocampal CA3 pyramidal neurons.J. Physiol. 2009; 587: 1265-1281Crossref PubMed Scopus (59) Google Scholar) across the range of 10–50 Hz (Shao and Dudek, 2009Shao L.R. Dudek F.E. Both synaptic and intrinsic mechanisms underlie the different properties of population bursts in the hippocampal CA3 area of immature versus adult rats.J. Physiol. 2009; 587: 5907-5923Crossref PubMed Scopus (16) Google Scholar) (Figure 2A , Naive, black). The same conditioning paradigm reduced CA3 neuron excitability so that each EPSP triggered a maximum of one AP (Figure 2A, PC, red), and output/input ratios became close to 1:1 (Figure 2B). The conditioning induced no change in evoked synaptic currents (Figure S1C), demonstrating that this 10 Hz stimulation paradigm did not significantly influence synaptic strength (Dudek and Bear, 1992Dudek S.M. Bear M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.Proc. Natl. Acad. Sci. USA. 1992; 89: 4363-4367Crossref PubMed Scopus (1324) Google Scholar). The postsynaptic locus of this excitability change was again confirmed by testing excitability with injection of current steps: naive CA3 neurons fired multiple APs, increasing in numbers proportionally with depolarizing current injection (Figure 2C, Naive, black), but following synaptic conditioning, the current threshold for AP generation was raised (Figure 2C, PC, red) from 100 to over 300 pA. The PC-induced threshold rise was blocked by NMDAR antagonists (50 μM AP-5, 10 μM MK801 applied for the 1 hr conditioning) and mimicked by perfusion of NO donors (Figure 2D), consistent with a nitrergic decrease in excitability. These results gave two general insights into the control of neuronal excitability: glutamatergic synaptic activity reduced excitability of the target neurons in the MNTB and CA3, and this was mediated by NO signaling. We next explored the mechanism of this postsynaptic excitability change using whole-cell voltage clamp. Under voltage clamp, MNTB neurons exhibited a mean outward current of 23 ± 1 nA at +50 mV (Figure 3A , Ctrl, n = 10), of which one-third was blocked by the Kv3 antagonist TEA (1 mM), confirming Kv3 contribution (Figure 3A, TEA, n = 7) and consistent with previous reports (Macica and Kaczmarek, 2001Macica C.M. Kaczmarek L.K. Casein kinase 2 determines the voltage dependence of the Kv3.1 channel in auditory neurons and transfected cells.J. Neurosci. 2001; 21: 1160-1168Crossref PubMed Google Scholar). Following synaptic conditioning, the outward current increased to 59 ± 4 nA (Figure 3B, PC, n = 17; p < 0.0001, unpaired data). This large increase in conductance was blocked by antagonism of both NMDARs and AMPARs during the conditioning period (Figure 3B, PC+AP5/MK+CNQX, n = 6). Likewise, voltage clamp of CA3 neurons showed control outward currents of 21 ± 2 nA (Figure 3E, n = 10, at +50 mV) that increased to 38 ± 2 nA after conditioning (Figure 3F, n = 6; p = 0.0005, unpaired data). NMDAR inhibition during conditioning also blocked the K+ current potentiation in the CA3 neurons (Figure 3F, n = 6). In both the MNTB and CA3 neurons, inhibition of nNOS by 7-nitroindazole (7-NI, 10 μM) during conditioning also blocked the K+ current potentiation (Figures 3C and 3G). Under control naive conditions, CA3 HVA currents of 21 ± 2 nA were sensitive to 1 mM TEA (Figure 3E, 12 ± 1 nA, 43% reduction at +50 mV). Iberiotoxin (Ibtx; 100 nM) block of BK channels caused only minor suppression of whole-cell currents (Figure 3E, 18 ± 1 nA, 14% reduction at +50 mV), whereas subsequent application of 1 mM TEA substantially reduced outward currents to 11 ± 1 nA (not shown, n = 5), consistent with Kv3 contributing approximately 29% of total outward current. The Kv2-gating modifier r-stromatoxin-1 (300 nM) (Escoubas et al., 2002Escoubas P. Diochot S. Célérier M.L. Nakajima T. Lazdunski M. Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies.Mol. Pharmacol. 2002; 62: 48-57Crossref PubMed Scopus (150) Google Scholar, Guan et al., 2007Guan D. Tkatch T. Surmeier D.J. Armstrong W.E. Foehring R.C. Kv2 subunits underlie slowly inactivating potassium current in rat neocortical pyramidal neuron" @default.
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• W2004694849 date "2011-07-01" @default.
• W2004694849 modified "2023-09-30" @default.
• W2004694849 title "Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability" @default.
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• W2004694849 doi "https://doi.org/10.1016/j.neuron.2011.05.037" @default.
• W2004694849 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3245892" @default.
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