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• W2088069957 abstract "The dynamics of inhibitory circuits in the cortex is thought to rely mainly on synaptic modifications. We challenge this view by showing that hippocampal parvalbumin-positive basket cells (PV-BCs) of the CA1 region express long-term (>30 min) potentiation of intrinsic neuronal excitability (LTP-IEPV-BC) upon brief repetitive stimulation of the Schaffer collaterals. LTP-IEPV-BC is induced by synaptic activation of metabotropic glutamate receptor subtype 5 (mGluR5) and mediated by the downregulation of Kv1 channel activity. LTP-IEPV-BC promotes spiking activity at the gamma frequency (∼35 Hz) and facilitates recruitment of PV-BCs to balance synaptic and intrinsic excitation in pyramidal neurons. In conclusion, activity-dependent modulation of intrinsic neuronal excitability in PV-BCs maintains excitatory-inhibitory balance and thus plays a major role in the dynamics of hippocampal circuits. The dynamics of inhibitory circuits in the cortex is thought to rely mainly on synaptic modifications. We challenge this view by showing that hippocampal parvalbumin-positive basket cells (PV-BCs) of the CA1 region express long-term (>30 min) potentiation of intrinsic neuronal excitability (LTP-IEPV-BC) upon brief repetitive stimulation of the Schaffer collaterals. LTP-IEPV-BC is induced by synaptic activation of metabotropic glutamate receptor subtype 5 (mGluR5) and mediated by the downregulation of Kv1 channel activity. LTP-IEPV-BC promotes spiking activity at the gamma frequency (∼35 Hz) and facilitates recruitment of PV-BCs to balance synaptic and intrinsic excitation in pyramidal neurons. In conclusion, activity-dependent modulation of intrinsic neuronal excitability in PV-BCs maintains excitatory-inhibitory balance and thus plays a major role in the dynamics of hippocampal circuits. The dynamics of inhibitory circuits is thought to rely on synaptic modifications Results show that basket cells express persistent increase in neuronal excitability This plasticity depends on mGluR5 and involves the regulation of Kv1 channels This plasticity facilitates recruitment of basket cells to balance excitation Excitation and inhibition walk hand in hand in cortical circuits (Isaacson and Scanziani, 2011Isaacson J.S. Scanziani M. How inhibition shapes cortical activity.Neuron. 2011; 72: 231-243Abstract Full Text Full Text PDF PubMed Scopus (979) Google Scholar). This excitatory-inhibitory balance is thought to maintain activity within physiological bounds and shape cortical activity in space and time. Excitatory-inhibitory balance can be transiently perturbed by learning but generally recovers after a few tens of minutes (Froemke et al., 2007Froemke R.C. Merzenich M.M. Schreiner C.E. A synaptic memory trace for cortical receptive field plasticity.Nature. 2007; 450: 425-429Crossref PubMed Scopus (430) Google Scholar). Classically, activity-dependent plasticity of inhibitory circuits is thought to be achieved by the persistent enhancement of excitatory synaptic drive to inhibitory interneurons (Alle et al., 2001Alle H. Jonas P. Geiger J.R. PTP and LTP at a hippocampal mossy fiber-interneuron synapse.Proc. Natl. Acad. Sci. USA. 2001; 98: 14708-14713Crossref PubMed Scopus (132) Google Scholar; Kullmann and Lamsa, 2007Kullmann D.M. Lamsa K.P. Long-term synaptic plasticity in hippocampal interneurons.Nat. Rev. Neurosci. 2007; 8: 687-699Crossref PubMed Scopus (235) Google Scholar; Kullmann et al., 2012Kullmann D.M. Moreau A.W. Bakiri Y. Nicholson E. Plasticity of inhibition.Neuron. 2012; 75: 951-962Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar; Lamsa et al., 2007Lamsa K.P. Heeroma J.H. Somogyi P. Rusakov D.A. Kullmann D.M. Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.Science. 2007; 315: 1262-1266Crossref PubMed Scopus (187) Google Scholar; Maccaferri et al., 1998Maccaferri G. Tóth K. McBain C.J. Target-specific expression of presynaptic mossy fiber plasticity.Science. 1998; 279: 1368-1370Crossref PubMed Scopus (184) Google Scholar; Pelletier and Lacaille, 2008Pelletier J.G. Lacaille J.C. Long-term synaptic plasticity in hippocampal feedback inhibitory networks.Prog. Brain Res. 2008; 169: 241-250Crossref PubMed Scopus (36) Google Scholar). For instance, feed-forward and feedback interneurons in the CA1 region of the hippocampus both express long-term synaptic potentiation (Lamsa et al., 2005Lamsa K. Heeroma J.H. Kullmann D.M. Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination.Nat. Neurosci. 2005; 8: 916-924Crossref PubMed Scopus (137) Google Scholar; Lamsa et al., 2007Lamsa K.P. Heeroma J.H. Somogyi P. Rusakov D.A. Kullmann D.M. Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit.Science. 2007; 315: 1262-1266Crossref PubMed Scopus (187) Google Scholar). However, functional plasticity might also be achieved through the regulation of voltage-gated ion channels that control synaptic integration and spike initiation (Debanne and Poo, 2010Debanne D. Poo M.M. Spike-timing dependent plasticity beyond synapse - pre- and post-synaptic plasticity of intrinsic neuronal excitability.Front. Synaptic Neurosci. 2010; 2: 21PubMed Google Scholar; Zhang and Linden, 2003Zhang W. Linden D.J. The other side of the engram: experience-driven changes in neuronal intrinsic excitability.Nat. Rev. Neurosci. 2003; 4: 885-900Crossref PubMed Scopus (629) Google Scholar). Persistent activity-dependent plasticity of intrinsic neuronal excitability has been reported in CA1 hippocampal principal cells (Campanac et al., 2008Campanac E. Daoudal G. Ankri N. Debanne D. Downregulation of dendritic I(h) in CA1 pyramidal neurons after LTP.J. Neurosci. 2008; 28: 8635-8643Crossref PubMed Scopus (77) Google Scholar; Campanac and Debanne, 2008Campanac E. Debanne D. Spike timing-dependent plasticity: a learning rule for dendritic integration in rat CA1 pyramidal neurons.J. Physiol. 2008; 586: 779-793Crossref PubMed Scopus (96) Google Scholar; Daoudal et al., 2002Daoudal G. Hanada Y. Debanne D. Bidirectional plasticity of excitatory postsynaptic potential (EPSP)-spike coupling in CA1 hippocampal pyramidal neurons.Proc. Natl. Acad. Sci. USA. 2002; 99: 14512-14517Crossref PubMed Scopus (124) Google Scholar; Wang et al., 2003Wang Z. Xu N.L. Wu C.P. Duan S. Poo M.M. Bidirectional changes in spatial dendritic integration accompanying long-term synaptic modifications.Neuron. 2003; 37: 463-472Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) but whether GABAergic interneurons express use-dependent intrinsic plasticity has yet to be addressed (Miles and Poncer, 1993Miles R. Poncer J.C. Metabotropic glutamate receptors mediate a post-tetanic excitation of guinea-pig hippocampal inhibitory neurones.J. Physiol. 1993; 463: 461-473PubMed Google Scholar; Miller et al., 2011Miller M.N. Okaty B.W. Kato S. Nelson S.B. Activity-dependent changes in the firing properties of neocortical fast-spiking interneurons in the absence of large changes in gene expression.Dev. Neurobiol. 2011; 71: 62-70Crossref PubMed Scopus (27) Google Scholar; Ross and Soltesz, 2001Ross S.T. Soltesz I. Long-term plasticity in interneurons of the dentate gyrus.Proc. Natl. Acad. Sci. USA. 2001; 98: 8874-8879Crossref PubMed Scopus (64) Google Scholar; Sun, 2009Sun Q.Q. Experience-dependent intrinsic plasticity in interneurons of barrel cortex layer IV.J. Neurophysiol. 2009; 102: 2955-2973Crossref PubMed Scopus (56) Google Scholar; Yazaki-Sugiyama et al., 2009Yazaki-Sugiyama Y. Kang S. Câteau H. Fukai T. Hensch T.K. Bidirectional plasticity in fast-spiking GABA circuits by visual experience.Nature. 2009; 462: 218-221Crossref PubMed Scopus (164) Google Scholar). We show here that in area CA1 feed-forward inhibition is mostly enhanced by high-frequency stimulation of the Schaffer collaterals through a persistent increase in intrinsic neuronal excitability in a subset of GABAergic interneurons of the CA1 region. This intrinsic plasticity requires synaptic stimulation of metabotropic glutamate receptor type 5 and is mediated by the downregulation of voltage-gated potassium channels. We recorded from CA1 pyramidal neurons in hippocampal slice (see Experimental Procedures). Compound excitatory and inhibitory postsynaptic potentials were evoked by stimulation of the Schaffer collaterals (Figure 1A; see Figure S1 available online). High-frequency stimulation (HFS) of the Schaffer collaterals (10 trains of 10 pulses at 100 Hz, delivered at a frequency of 0.3 Hz) resulted not only in potentiation of synaptic excitation, but also increased disynaptic inhibition in CA1 pyramidal neurons (Figure 1A). Monosynaptic excitatory postsynaptic potentials (EPSPs) onto interneurons that are initially subthreshold may cross the spike threshold after HFS. In order to test this hypothesis, fast-spiking interneurons were recorded in whole-cell configuration in the stratum pyramidale of the CA1 region (see Experimental Procedures). Their resting membrane potential was −67.6 ± 0.7 mV (n = 12). The great majority of these cells were parvalbumin-positive (10/12; Figure 1B). Their axonal arborization, labeled with biocytin, was confined within the pyramidal cell layer (9/9; Figure 1B), indicating that they were putative parvalbumin-positive basket cells (PV-BCs; (Freund and Katona, 2007Freund T.F. Katona I. Perisomatic inhibition.Neuron. 2007; 56: 33-42Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar; Glickfeld and Scanziani, 2006Glickfeld L.L. Scanziani M. Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells.Nat. Neurosci. 2006; 9: 807-815Crossref PubMed Scopus (172) Google Scholar; Gulyás et al., 2010Gulyás A.I. Szabó G.G. Ulbert I. Holderith N. Monyer H. Erdélyi F. Szabó G. Freund T.F. Hájos N. Parvalbumin-containing fast-spiking basket cells generate the field potential oscillations induced by cholinergic receptor activation in the hippocampus.J. Neurosci. 2010; 30: 15134-15145Crossref PubMed Scopus (186) Google Scholar; Szabó et al., 2010Szabó G.G. Holderith N. Gulyás A.I. Freund T.F. Hájos N. Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.Eur. J. Neurosci. 2010; 31: 2234-2246Crossref PubMed Scopus (68) Google Scholar)). PV-BCs typically fired action potentials (APs) in clusters and the first spike, upon a slow depolarizing ramp, occurred generally with a delay (Goldberg et al., 2008Goldberg E.M. Clark B.D. Zagha E. Nahmani M. Erisir A. Rudy B. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.Neuron. 2008; 58: 387-400Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). We first examined whether recruitment of PV-BCs was altered after HFS. Initially, the probability of evoking an AP by the synaptic input was very low (0.07 ± 0.06, n = 5), indicating that they were not recruited by excitatory inputs before HFS. In contrast, the firing probability markedly increased 15–30 min after HFS (to 0.50 ± 0.15, n = 5; Wilcoxon, p < 0.07; Figure 1C), showing that PV-BCs were recruited by the stimulated synaptic pathway. We next examined whether the origin of this increased firing was synaptic or intrinsic. Excitatory synaptic transmission was found to be enhanced after HFS (155% ± 7% of the control EPSP slope, n = 5; Figure 1D), suggesting that the observed facilitation in spiking activity may partly result from facilitation in synaptic excitation. To determine whether intrinsic excitability was enhanced in PV-BCs, synaptic circuits were bypassed by directly simulating families of near-threshold EPSPs in PV-BC with the dynamic-clamp technique (Figure 1E). The input-output function of PV-BCs was found to be strengthened 15–30 min after HFS (Figure 1E). These data indicate that intrinsic neuronal excitability of PV-BC is persistently enhanced, independently of any modification in excitatory synaptic circuits. Next, we estimated the respective contributions of synaptic and intrinsic changes in the recruitment of PV-BC after HFS. Synaptic and intrinsic changes were estimated from the EPSP-spike curves established before and 10–30 min after HFS. The firing probability was measured on the control and post-HFS curves for the initial value of EPSP-slope (3.4 mV/ms; gray arrow in Figure 1F) and for that obtained after HFS (5.4 mV/ms; red arrow in Figure 1F). The data indicate that a large proportion (∼80%) of the increased firing probability results from an increase in intrinsic excitability. In order to fully characterize the induction and expression mechanisms of this novel form of intrinsic plasticity in PV-BCs, moderate spiking activity (8–10 spikes) was triggered with pulses of depolarizing current (800 ms). To verify that the HFS-induced increase in intrinsic neuronal excitability did not result from a change in background GABAergic inhibition, experiments were performed in the presence of the GABAA channel blocker, picrotoxin (100 μM). After recording a stable baseline, high frequency stimulation (HFS) was delivered to the synaptic pathway. HFS produced a transient increase in spike number (247% ± 29% of the control, n = 9, measured at +1 min) followed by a stable plateau of enhanced excitability (209% ± 41% of the control spike number, n = 9, measured at 25–30 min; Figure 2A). While the short-term increase in excitability was associated with a transient depolarization of the membrane potential by ∼2–3 mV (104% ± 1% of the control membrane potential measured at +2 min), the long-term component (LTP-IEPV-BC) measured at 25–30 min was totally independent of any change in membrane potential (100.1% ± 0.5%, n = 9) or input resistance (99% ± 2%, n = 9). Other subthreshold parameters such as the membrane time constant (τm = 20.1 ± 2.4 ms before HFS and 20.4 ± 2.1 ms after, Wilcoxon p > 0.5; Figure S2) or the resonance properties (Figure S2) remained unchanged after induction of LTP-IEPV-BC. Firing accommodation was not altered after induction of LTP-IEPV-BC (first ISI / last ISI: 1.44 ± 0.27 before and 1.19 ± 0.11 after HFS; Wilcoxon p > 0.5). No change in excitability was observed in the absence of HFS (107% ± 1%, n = 7; Wilcoxon p > 0.05; Figure S2). Long-term synaptic modifications in hippocampal interneurons require a wide range of glutamate receptors including ionotropic and metabotropic glutamate receptors (Kullmann and Lamsa, 2007Kullmann D.M. Lamsa K.P. Long-term synaptic plasticity in hippocampal interneurons.Nat. Rev. Neurosci. 2007; 8: 687-699Crossref PubMed Scopus (235) Google Scholar; Pelletier and Lacaille, 2008Pelletier J.G. Lacaille J.C. Long-term synaptic plasticity in hippocampal feedback inhibitory networks.Prog. Brain Res. 2008; 169: 241-250Crossref PubMed Scopus (36) Google Scholar). To test whether AMPA or NMDA receptors are required for LTP-IEPV-BC induction, HFS was delivered in the presence of 2 mM kynurenate. Although the transient component was diminished (137% ± 7% of the control, n = 9, measured at +1 min), no significant reduction in LTP-IEPV-BC was observed (211% ± 20%, n = 11, measured at 25–30 min, Mann-Whitney U test, p > 0.2); Figure 2B), indicating that NMDA and AMPA receptor activation does not play a critical role in LTP-IEPV-BC. Next, the role of metabotropic glutamate receptor (mGluR) activation was tested. HFS failed to induce LTP-IEPV-BC in the presence of 2 mM kynurenate and 10 μM of the mGluR type 5-selective antagonist, MPEP (97% ± 11%, n = 9) or in the presence of MPEP alone (10 μM; 111% ± 7% n = 5; Mann-Whitney U test, p < 0.05; Figure 2C). LTP-IEPV-BC was also observed following brief application of the mGluR1/5 agonist, DHPG (20 μM; 169% ± 42%, n = 5) or the mGluR5 agonist CHPG (200–500 μM; 297% ± 72%, n = 9; Figure 3A). To verify that other neurotransmitter/neuromodulators were not necessary to the induction of LTP-IEPV-BC, experiments were performed in the presence of the broad spectrum calcium channel blocker cadmium. Cadmium (50 μM) totally abolished evoked synaptic responses. In the presence of cadmium, CHPG (500 μM) still induced an increase in excitability that was similar to that induced in control saline (199% ± 45%, n = 7, Mann-Whitney U test, p > 0.5; Figure 3B). Thus, although AMPA/NMDA receptors are involved in the short-term increase in excitability in PV-BCs, activation of mGluR5 is necessary and sufficient for the induction of LTP-IEPV-BC. We next investigated the expression mechanisms of LTP-IEPV-BC. Fast spiking PV-BCs display delayed firing, which is a typical hallmark of the slowly inactivating D-type K+ current mediated by Kv1 channels (Cudmore et al., 2010Cudmore R.H. Fronzaroli-Molinieres L. Giraud P. Debanne D. Spike-time precision and network synchrony are controlled by the homeostatic regulation of the D-type potassium current.J. Neurosci. 2010; 30: 12885-12895Crossref PubMed Scopus (69) Google Scholar; Goldberg et al., 2008Goldberg E.M. Clark B.D. Zagha E. Nahmani M. Erisir A. Rudy B. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.Neuron. 2008; 58: 387-400Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar; Li et al., 2012Li K.X. Lu Y.M. Xu Z.H. Zhang J. Zhu J.M. Zhang J.M. Cao S.X. Chen X.J. Chen Z. Luo J.H. et al.Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy.Nat. Neurosci. 2012; 15: 267-273Crossref Scopus (123) Google Scholar). A striking feature of LTP-IEPV-BC induced by HFS or application of mGluR agonist is the marked reduction (∼50%) in the latency of the first spike (Figures 4A and 4B ). The temporal change in firing was analyzed on spike histograms. In fact, both phasic (100–300 ms) and tonic spiking activity increased (Figure 4C). The reduced delay in the first spike latency suggests that the D-type potassium current (ID) carried by Kv1 channel is downregulated following LTP-IEPV-BC induction. In fact, PV-positive interneurons in the stratum pyramidale were found to express high levels of Kv1.1 (Figure 5A) and Kv1.2 (Figure S3) channels in both the cell body and their axon initial segment (AIS). Blocking Kv1 channels with 4-AP (5–10 μM) or DTx-I (100–150 nM) reduced the first spike latency (21% ± 11% of the control, n = 15) and strongly increased spiking activity (402% ± 45% of the control spike number, n = 15; Figure 5B), thus mimicking LTP-IEPV-BC. The reduced delay in the first spike suggests that the D-type potassium current (ID) carried by Kv1 channel is downregulated following LTP-IEPV-BC induction. If this hypothesis is correct, LTP-IEPV-BC should be occluded by the pharmacological inactivation of ID. In fact, in the presence of 100–150 nM DTx-I or 5–10 μM 4-AP, HFS failed to induce LTP-IEPV-BC (102% ± 8%, n = 7, and 106% ± 4%, n = 5, respectively; Figures 5C and S3). In these experiments, the amplitude of the current step was adjusted to elicit a non-saturating number of spikes in control conditions (8–10 spikes/s; Figures 5C and S3). Furthermore, the delay to the first spike remained unchanged in the presence of Kv1 channel blockers (4-AP: 89% ± 8%, n = 5, and DTx-I: 126% ± 22%, n = 7; Figure S3), indicating that all features of LTP-IEPV-BC are suppressed when Kv1 channels are blocked. We next examined the cellular mechanism of mGluR5-dependent regulation of Kv1. The translation of Kv1.1 channel mRNA and surface expression of Kv1.1 channels is strongly inhibited by the mammalian target of rapamycin mTOR (Raab-Graham et al., 2006Raab-Graham K.F. Haddick P.C. Jan Y.N. Jan L.Y. Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites.Science. 2006; 314: 144-148Crossref PubMed Scopus (217) Google Scholar). mTOR is also activated by mGluR5 through the PI3K/Akt pathway (Klann and Dever, 2004Klann E. Dever T.E. Biochemical mechanisms for translational regulation in synaptic plasticity.Nat. Rev. Neurosci. 2004; 5: 931-942Crossref PubMed Scopus (339) Google Scholar). We therefore tested whether LTP-IEPV-BC was affected by the inhibition of mTOR with rapamycin. LTP-IEPV-BC was significantly reduced in PV-BCs treated for 2 hr with rapamycin (50 nM; 122% ± 20%, n = 5, versus 212% ± 29%, n = 8, Wilcoxon, p < 0.07; Figure 5D). We conclude that LTP-IEPV-BC is expressed through an mGluR5-dependent downregulation of Kv1 channel activity involving mTOR. Kv1 channels are generally localized at the AIS where they control the spike threshold (Goldberg et al., 2008Goldberg E.M. Clark B.D. Zagha E. Nahmani M. Erisir A. Rudy B. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.Neuron. 2008; 58: 387-400Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar; Higgs and Spain, 2011Higgs M.H. Spain W.J. Kv1 channels control spike threshold dynamics and spike timing in cortical pyramidal neurones.J. Physiol. 2011; 589: 5125-5142PubMed Google Scholar; Nusser, 2009Nusser Z. Variability in the subcellular distribution of ion channels increases neuronal diversity.Trends Neurosci. 2009; 32: 267-274Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). We therefore examined whether changes in spike threshold occurred following induction of LTP-IEPV-BC. As reported earlier, the voltage threshold of the first AP was relatively depolarized (−35.7 ± 1.1 mV, n = 9). It is noteworthy that the spike threshold was found to be hyperpolarized by 3.9 ± 1.1 mV (n = 9), 15–30 min after HFS (Figure 6A). These data indicate that the global responsiveness of PV-BCs is enhanced following HFS and that subthreshold EPSPs might be able to elicit an action potential after induction of LTP-IEPV-BC. The HFS-induced hyperpolarization of the spike threshold was perfectly mimicked by pharmacological inactivation of Kv1 channels with DTx-I. The voltage threshold of the first AP was hyperpolarized by 11.1 ± 1.1 mV (n = 9) in the presence of DTx-I (Figure 6B). Similar changes in firing profile were obtained in a model of PV-BC upon blockade of Kv1 channels at the axon or the cell body (Figure S4), suggesting that regulation of axonal or somatic Kv1 channels may equally account for LTP-IEPV-BC (Golomb et al., 2007Golomb D. Donner K. Shacham L. Shlosberg D. Amitai Y. Hansel D. Mechanisms of firing patterns in fast-spiking cortical interneurons.PLoS Comput. Biol. 2007; 3: e156Crossref PubMed Scopus (83) Google Scholar). However, change in spike threshold reached the level observed experimentally only if Kv1 channels were suppressed in the axon. In order to further confirm that PV-BC recruitment was enhanced by the Kv1-dependent hyperpolarization of the spike threshold, we examined the effect of the pharmacological blockade of Kv1 on disynaptic inhibition. As expected, DTx-I mimicked the effect of HFS by increasing disynaptic inhibition in CA1 pyramidal neurons (Figure 6C). Interestingly, the enhanced disynaptic inhibition induced by HFS or by CHPG was importantly reduced or occluded by DTx-I (HFS; 186% ± 13%, n = 6, versus 323% ± 19%, n = 7, in control; CHPG: 96% ± 8%, n = 7, versus 147% ± 8%, n = 7, in control; Figure 6D). Thus, these data confirm that the facilitation of feed-forward inhibition is predominantly mediated by the regulation of intrinsic excitability. We conclude that mGluR5 and Kv1-dependent LTP-IEPV-BC promote disynaptic inhibition in CA1 circuits. Fast-spiking PV-BCs display a specific mode of firing composed of sparse and clustered APs (Goldberg et al., 2008Goldberg E.M. Clark B.D. Zagha E. Nahmani M. Erisir A. Rudy B. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.Neuron. 2008; 58: 387-400Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Sparse spikes (Sps) typically occurred in our recordings after a slow depolarizing ramp of potential at an instantaneous frequency of ∼10 Hz (Figures 7A and S5). In contrast, clustered spikes (Cls) followed immediately an AP and displayed a much more hyperpolarized voltage threshold. Consequently, their instantaneous frequency was much higher and corresponded to the gamma (γ)-frequency range (25–50 Hz). We therefore examined whether Sps and Cls were equally altered following induction of LTP-IEPV-BC. Surprisingly, the enhanced excitability was mostly supported by an increase in the proportion of Cls (from 69% ± 9% to 92% ± 3%; Figure 7A). In fact, a clear gain of spiking activity in the γ frequency range was observed after HFS (Figure 7B). In order to check that the observed changes were not dependent on the type of depolarizing profile, trains of simulated EPSPs were injected in PV-BCs. A similar increase in the γ range was observed after HFS (Figure S5). Thus, mGluR5 stimulation increases intrinsic neuronal excitability of PV-BC and promotes their firing in the γ range. We next determined whether HFS-induced increase in intrinsic excitability was specific to PV-BCs. A second class of interneuron was recorded in the stratum pyramidale of the CA1 region. In contrast to PV-BCs, these interneurons fired regularly (CV of the fifth interspike interval 0.04 ± 0.01, n = 25 versus 0.67 ± 0.10, n = 27 for PV-BCs; Figure 8A), displayed a high input resistance (476 ± 48 MΩ, n = 20 versus 120 ± 9 MΩ n = 22 for PV-BCs, Mann-Whitney U test p < 0.01) and had a low rheobase (56 ± 5 pA, n = 20 versus 204 ± 13 pA, n = 22 for PV-BCs, Mann-Whitney U test, p < 0.01). None of regular spiking (RS) neurons expressed PV (0/13; Figure 8B). Most importantly, HFS failed to induce LTP-IE in these interneurons (91% ± 4%, n = 7; Figure 8C). Furthermore, bath application of the type I mGluR agonist, DHPG (20 μM) or the specific mGluR5 agonist CHPG (200–500 μM) induced no increase in intrinsic excitability (91% ± 11%, n = 7, and 80% ± 7%, n = 7; Figure S6). Taken together, these results indicate that LTP-IE is specifically expressed in CA1 PV-BCs. We report here an unexpected form of intrinsic plasticity in PV-BCs of the CA1 region. In addition to the short-term increase in excitability reported earlier (Miles and Poncer, 1993Miles R. Poncer J.C. Metabotropic glutamate receptors mediate a post-tetanic excitation of guinea-pig hippocampal inhibitory neurones.J. Physiol. 1993; 463: 461-473PubMed Google Scholar), HFS also induced a persistent increase in intrinsic neuronal excitability (LTP-IEPV-BC). LTP-IEPV-BC has two major functional consequences. Together with synaptic modification, LTP-IEPV-BC facilitates feed-forward inhibition in CA1 circuits. In addition, it promotes firing in the gamma range. Interestingly, this intrinsic plasticity was absent in another class of parvalbumin-negative interneurons which display regular firing. We show here that HFS of the Schaffer collateral induced a persistent increase in feed-forward inhibition in CA1 pyramidal neurons. The enhanced recruitment of inhibition is likely to be achieved by an increase in the intrinsic excitability of PV-BCs. Initially, PV-BCs are almost silent because of their low input resistance (∼120 MΩ for constant depolarization, but only ∼50 MΩ for oscillatory input at 40 Hz [Figure S2]) and their depolarized spike threshold (−37 mV). Similar values of spike threshold have been reported in PV interneurons (Goldberg et al., 2008Goldberg E.M. Clark B.D. Zagha E. Nahmani M. Erisir A. Rudy B. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons.Neuron. 2008; 58: 387-400Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). The depolarized spike threshold essentially results from the high level of Kv conductance. Blockade of Kv1 channels with DTx-I hyperpolarizes the spike threshold by 11 mV (Figure 6B). Although both synaptic and intrinsic changes contribute to the recruitment of GABAergic inhibition, intrinsic changes take a much larger part in this process. First, EPSP-spike curves reveal that the expected increase in spiking activity resulting from pure synaptic changes is limited to ∼20% whereas intrinsic changes represent ∼80% (Figure 1F). In addition, when Kv1 channels are blocked with DTx-I, the remaining increase in HFS-induced feed-forward inhibition represents only 39% of the control increase, confirming that more than 60% result from modulation of intrinsic excitability. Thus, intrinsic changes represent a powerful means of recruiting PV-BC interneurons in CA1 circuits. HFS of the Schaffer collaterals induced two types of changes in PV-BCs: a short-term increase followed by a plateau of potentiation. The short-term enhancement is concomitant with a postsynaptic depolarization and is also observed upon application of mGluR agonists. This initial component was markedly reduced in the presence of kynurenate. A possible explanation is that the total amount of glutamate release during HFS is reduced in the presence of kynurenate because polysynaptic circuits are most likely blocked. Long-lasting increase in excitability, resulting from persistent cell depolarization has been reported in basket cells of the dentate gyrus (Ross and Soltesz, 2001Ross S.T. Soltesz I. Long-term plasticity in interneurons of the dentate gyrus.Proc. Natl. Acad. Sci. USA. 2001; 98: 8874-8879Crossref PubMed Scopus (64) Google Scholar). In contrast, LTP-IEPV-BC in the CA1 region is independent of any depolarization of the recorded neuron. We show that LTP-IEPV-BC is mediated by an mGluR5-dependent reduction in Kv1 channel activity, possibly resulting from the mTOR-dependent disruption of Kv1.1 channel turnover (Raab-Graham et al., 2006Raab-Graham K.F. Haddick P.C. Jan Y.N. Jan L.Y. Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites.Scien" @default.
• W2088069957 created "2016-06-24" @default.
• W2088069957 creator A5025832347 @default.
• W2088069957 creator A5043930558 @default.
• W2088069957 creator A5049020593 @default.
• W2088069957 creator A5052592152 @default.
• W2088069957 creator A5056479130 @default.
• W2088069957 creator A5069299504 @default.
• W2088069957 date "2013-02-01" @default.
• W2088069957 modified "2023-10-14" @default.
• W2088069957 title "Enhanced Intrinsic Excitability in Basket Cells Maintains Excitatory-Inhibitory Balance in Hippocampal Circuits" @default.
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