Ingrid van Welie et al- Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal...

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95:2007-2012, 2006. First published Nov 23, 2005; doi:10.1152/jn.00220.2005J NeurophysiolIngrid van Welie, Johannes A. van Hooft and Wytse J. Wadman

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Report

Background Activity Regulates Excitability of Rat Hippocampal CA1

Pyramidal Neurons by Adaptation of a K Conductance

Ingrid van Welie, Johannes A. van Hooft, and Wytse J. Wadman

Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands

Submitted 1 March 2005; accepted in final form 18 November 2005

Van Welie, Ingrid, Johannes A. van Hooft, and Wytse J. Wad-man. Background activity regulates excitability of rat hippocampalCA1 pyramidal neurons by adaptation of a K conductance. J Neu-rophysiol 95: 20072012, 2006. First published November 23, 2005;doi:10.1152/jn.00220.2005. In the in vivo brain background synapticactivity has a strong modulatory influence on neuronal excitability.Here we report that in rat hippocampal slices, blockade of endogenousin vitro background activity results in an increased excitability of CA1pyramidal neurons within tens of minutes. The increase in excitabilityconstitutes a leftward shift in the inputoutput relationship of pyra-

midal neurons, indicating a reduced threshold for the induction ofaction potentials. The increase in excitability results from an adaptivedecrease in a sustained K conductance, as recorded from somaticcellattached patches. After 20 min of blockade of background activ-ity, the mean sustained K current amplitude in somatic patches wasreduced to 46 9% of that in time-matched control patches. Blockadeof background activity did not affect fast Na conductance. Together,these results suggests that the reduction in K conductance serves asan adaptive mechanism to increase the excitability of CA1 pyramidalneurons in response to changes in background activity such that thedynamic range of the inputoutput relationship is effectively maintained.

I N T R O D U C T I O N

Synaptic background activity in vivo is the main source ofvariance in membrane conductance and membrane voltage andtherefore determines the probability of firing of the postsynap-tic neuron (Destexhe and Pare 1999; Destexhe et al. 2003; Pareet al. 1998). Several in vivo and modeling studies have pro-vided a theoretical framework on the functional role for back-ground synaptic activity. It has been suggested that tonicbackground activity affects dendritic integration by keepingmembrane resistance low and therefore reducing neuronalresponsiveness (Bernander et al. 1991; Destexhe and Pare1999; Holmes and Woody 1989; Pare et al. 1998). Anothermodeling study (Ho and Destexhe 2000) that focused on theeffects of background activity on both membrane conductanceand membrane voltage fluctuations predicted that the presence

of high-amplitude membrane fluctuations enhances neuronalresponsiveness. Experimental studies in which these differentaspects of background activity were studied in detail showedthat either the effect of background activity on membranefluctuations alone (Fellous et al. 2003; Shu et al. 2003) or theeffects on membrane conductance and membrane fluctuationstogether (Chance et al. 2002) affect the gain of neuronalinputoutput relationships.

These studies show how background activity can influencepostsynaptic responsiveness and therefore determine the input

output gain of a neuron, although they do not consider thepotential role of activity-dependent adaptive gain-settingmechanisms that dynamically control excitability whenchanges in background activity occur. Considerable changes inbackground activity will shift the dynamic range of the neu-ronal input output relationship such that neuronal responsive-ness might be restricted to a limited range of synaptic inputs.This gain-setting problem could be resolved by adapting neu-ronal gain to the new level of background activity by modu-

lation of voltage-gated conductances. Several of such gain-setting mechanisms exist and it is becoming increasingly ap-parent that they operate at different timescales. Long-lastingchanges in synaptic activity at a timescale of hours to severaldays induce changes in voltage-gated ionic conductances in ahomeostatic manner (Aptowicz et al. 2004; Baines et al. 2001;Desai et al. 1999; Golowasch et al. 1999; Turrigiano et al.1995). Recent studies, however (Baines et al. 2003; Misonou etal. 2004; Nelson et al. 2003; van Welie et al. 2004), show thatactivity-induced adaptive mechanisms of neuronal excitabilitythat engage on a timescale of minutes also exist. These exper-imental findings suggest that, both in vitro and in vivo, rela-tively rapid changes in background activity could induce adap-tive gain-setting mechanisms by modulation of voltage-gatedion channels.

Background activity in vitro is much lower than that in vivo(Pare et al. 1998) but it is nevertheless present. We investigatedwhether the excitability of hippocampal CA1 pyramidal neu-rons in vitro is affected by blocking background activity. Weshow that blockade of background activity induces an adaptivereduction in a sustained K conductance with no significantactivity-dependent changes in Na conductance, resulting inan increased neuronal excitability. We conclude that acutechanges in the level of background activity in vitro can inducean adaptive modulation of a voltage-gated K conductancethat serves to reset the dynamic range of the input outputrelationship of CA1 pyramidal neurons.

M E T H O D S

Parasagittal slices of the hippocampus (250300 m) were pre-pared from 14- to 21-day-old male Wistar rats (Harlan, Zeist, TheNetherlands). Experiments were conducted according to the ethicscommittee guidelines of animal experimentation of the University ofAmsterdam. After decapitation, the brain was rapidly removed andplaced in ice-cold artificial cerebrospinal fluid (ACSF) containing (inmM): NaCl, 120; KCl, 3.5; CaCl

2, 2.5; MgSO

4, 1.3; NaH

2PO

4, 1.25;

glucose, 25; NaHCO3

, 25, equilibrated with 95% O2

-5% CO2

(pH

Address for reprint requests and other correspondence: W. J. Wadman,SILSCenter for Neuroscience, University of Amsterdam, P.O. Box 94084,1090 GB Amsterdam, The Netherlands (E-mail: [email protected]).

The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked advertisementin accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

J Neurophysiol 95: 20072012, 2006.First published November 23, 2005; doi:10.1152/jn.00220.2005.

20070022-3077/06 $8.00 Copyright 2006 The American Physiological Societywww.jn.org


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7.4). Subsequently, slices were cut using a vibroslicer (VT1000S,Leica Microsystems, Nussloch, Germany) and were allowed to re-cover for 1 h at 31C.

CA1 pyramidal neurons were visualized using an upright micro-scope (Zeiss Axioskop, Oberkochen, Germany) with Dodt contrastoptics (Luigs and Neumann, Ratingen, Germany) and with a VX44CCD camera (PCO, Kelheim, Germany). Patch-clamp recordingswere made at room temperature. For perforated patch recordings,patch pipettes were pulled from borosilicate glass and had a resistanceof 24 M when filled with (in mM): K-gluconate, 120; KCl, 20;HEPES, 10; MgSO

4, 1; and sucrose, 10 (pH 7.4 with KOH).

Gramicidin (100 g/ml, dissolved in DMSO; final DMSO concentra-tion in the pipette solution 0.01%) was added from a fresh stocksolution. Input resistance and series resistance were monitoredthroughout perforated patch recordings to monitor whether the cellentered the whole cell configuration. For whole cell somatic record-ings, pipettes were filled with (in mM): K-gluconate, 105; KCl, 30;HEPES, 10; EGTA, 5; CaCl

2, 0.5; and Mg-ATP, 2 (pH 7.4 with

KOH). Series resistance was 620 M during whole cell recordingsand was compensated for 80%. No correction was made for liquid

junction potentials. For cell-attached K current recordings, pipetteshad a resistance of 1.53 M and were filled with (in mM): NaCl,

120; HEPES, 10; KCl, 3; MgCl2, 1; and tetrodotoxin, 0.001 (pH 7.4with NaOH). For cell-attached Na current recordings, pipettes werefilled with (in mM): NaCl, 120; HEPES, 10; CaCl

2, 2; KCl, 3; MgCl

2,

1; tetraethylammonium chloride (TEA-Cl), 30; and 4-aminopyridine(4-AP), 15 (pH 7.4 with HCl). For cell-attached recordings, pipettecapacitance was reduced by wrapping pipettes in parafilm. Currentsignals in whole cell voltage clamp were acquired at 1 kHz andfiltered at 500 Hz and voltage signals in current clamp were acquiredat 10 kHz and filtered at 3.3 kHz using an EPC9 amplifier and Pulse8.31 software (HEKA Electronik, Lambrecht, Germany) run on anApple Mac G3 computer. During cell-attached K current recordings,current signals were acquired at 10 kHz and filtered at 3.33 kHz.During cell-attached Na current recordings, current signals wereacquired at 200 kHz and filtered at 66.7 kHz. Na currents wereaveraged over 10 consecutive sweeps. Fast synaptic background

activity was blocked by bath application of 100 M D-()-2-amino-5-phosphonopentanoic acid (AP5), 20 50 M 6-cyano-7-nitroqui-noxaline-2,3-dione disodium (CNQX) and 20100 M bicuculline-methochloride or bicuculline-methiodide. All chemicals were pur-chased from Tocris (Bristol, UK) or Sigma (Zwijndrecht, TheNetherlands).

The input resistance of CA1 pyramidal neurons was calculatedfrom voltage-responses to hyperpolarizing current injections given incurrent clamp (at t 750850 ms of the 1-s hyperpolarizing pulse).Synaptic events were detected and analyzed using a custom-madeprocedure in Igor (Wavemetrics, Lake Oswego, OR) as describedpreviously (van Hooft 2002). K currents were leak-corrected off-lineby using the calculated impedance from a 10-mV voltage step re-corded with each trace. K conductance (g) as a function of voltage(V) was calculated from I(V) using

gVIV

V Vrev(1)

where Vrev

is the reversal potential of K currents (90 mV). Theconductance (g) as a function of voltage (V) was fitted by a Boltzmannequation

gVgmax

1 expVh VVc

(2)

where gmax

is the maximal conductance, Vh

is the potential ofhalf-maximal activation, and V

cis the slope parameter. Na currents

were leak-corrected by a P/4 procedure. Na currents were fitted tothe GoldmanHodgkinKatz (GHK) current equation using a Boltz-

mann function to describe the voltage dependence of the sodiumpermeability

IV Vgmax

1 expVh VVc

Nain

Naout expV

1 expV(3)

with zF/RT and gmax

F[Na]out

P0

, where F is the Faradayconstant, R is the gas constant, T represents the absolute temperature,gmax

is the maximal conductance, and P0

is the maximal permeability.Note that in the cell-attached configuration, the pipette potential and

the resting membrane potential are in series to form the local trans-membrane potential, i.e., a pipette potential of 0 mV refers to theresting membrane potential. In this recording configuration, applyinga positive pipette potential results in membrane hyperpolarization andapplying a negative pipette potential results in membrane depolariza-tion. In the text and figures, we give membrane potentials relative tothe resting membrane potential, but we use the standard sign conven-tion that negative potentials indicate a hyperpolarization and positivepotentials indicate a depolarization. All values are given as means SE. Differences were tested by a Students t-test. P 0.05 is assumed

to indicate a significant difference.

R E S U L T S

To characterize the level of background activity in hip-pocampal slices, we recorded spontaneous synaptic events inthe whole cell patch-clamp configuration before and afterblockade of background activity. In control conditions, themean frequency of spontaneous synaptic events recorded fromCA1 pyramidal neurons for 1015 min at a holding potentialof 60 mV was 1.7 0.3 Hz (n 6). After blockade of-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptors, N-methyl-D-aspartate (NMDA) receptors, and-aminobutyric acid type A (GABA

A) receptors, which medi-

ate fast excitatory and inhibitory neurotransmission, by bathapplication of CNQX, AP5, and bicuculline, the mean fre-quency was reduced to 0.01 0.01 Hz (n 5, P 0.05, Fig.1A). Blockade of glutamatergic and GABAergic receptors wascomplete within 10 min and determination of the inputresistance of CA1 pyramidal neurons immediately on completeblock of synaptic events showed an increase in input resistanceof 10 8% (n 6).

To investigate whether background activity affects neuronalexcitability, we studied the firing properties of CA1 pyramidalneurons before and after blockade of background activity. Theperforated patch-clamp configuration was used to minimizeperturbation of the intracellular environment and signaling

pathways. After 1520 min of blockade of synaptic activity,the mean frequency of evoked action potentials in response toa 1-s depolarization had increased compared with control. Inresponse to the largest current injection of 90 pA, the firingfrequency had increased by 20 4% (n 4, Fig. 1B). Thisincrease was partly reversed on washing out of the AMPA-,NMDA-, and GABA

A-receptor antagonists. Concomitant with

the increase in firing frequency, CA1 neurons displayed aslight, nonsignificant, depolarized resting membrane potential(control: 57 3 mV, antagonists: 53 2 mV, wash:58 4 mV, n 4) and an increased input resistance(control: 248 20 M, antagonists: 337 43 M, n 4,P 0.05, Fig. 1C, wash: 315 3 M), which both partlyreversed on washout. The large increase in input resistance

Report

2008 I. VAN WELIE, J. A. VAN HOOFT, AND W. J. WADMAN

J Neurophysiol VOL 95 MARCH 2006 www.jn.org


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suggests that blockade of synaptic input leads to relativelyrapid changes in the intrinsic membrane properties of CA1pyramidal neurons. The increase in input resistance appearsadaptive in nature because plotting the firing frequency againstthe calculated membrane potential, which current injectionseffectively result in given the changes in input resistance,shows that the inputoutput relationship covers the samemembrane potential range in both conditions (Fig. 1D). Time

courses of the changes in firing frequency and input resistanceindicate that there is a gradual increase in both parametersduring the period of synaptic blockade (Fig. 1, E and F).

The intrinsic membrane properties of neurons are largelydetermined by voltage-gated conductances. We thus set out todetermine whether specific voltage-gated conductances weremodulated after blockade of background activity. Cell-attachedrecordings from the soma of CA1 pyramidal neurons weremade to investigate K conductances. K currents wereevoked by depolarizing patches to membrane potentials be-tween 10 and 150 mV after a conditioning hyperpolarizingprepulse of75 mV (all voltages given are relative to restingmembrane potential; see METHODS). Depolarization of patchestypically evoked a sustained outward current component,

which was often, but not in every patch, accompanied by a fasttransient component (Fig. 2A). Simultaneous bath applicationand inclusion of 10 mM 4-aminopyridine (4-AP) and 30 mMTEA-Cl in the pipette solution blocked both the fast, transientcomponent and the sustained component (data not shown).After 10 min of bath application of the AMPA-, NMDA-, andGABA

A-receptor antagonists, a significant decrease in sus-

tained K current amplitudes was apparent compared with

control recordings from separate patches in which ACSF wassuperfused. After 20 min of application of antagonists, sus-tained K current amplitudes were 46 9% of those intime-matched control patches (n 7, P 0.05, Fig. 2B). Atthis time point we also determined the activation curve of thesustained K current and normalized it to its own control at t0. For control patches, the mean maximal K conductance(g

max, Eq. 2) after 20 min of ACSF perfusion was 91 5% of

its value at t 0, whereas the K conductance after 20 min ofblockade of background activity was 52 11% of its value att 0 (n 7 for both conditions, P 0.05, Fig. 2C). Thepotential of half-maximal activation as well as the slope pa-rameter were not significantly different after blockade of back-ground activity compared with control (Fig. 2D). To test the

FIG. 1. Blockade of background synaptic activity increases excitability. A: spontaneous synaptic events were recorded in the whole cell patch-clampconfiguration in control condition and after bath application of antagonists for AMPA (2050 M CNQX), NMDA (100 M AP-5), and GABAA (20100 Mbicuculline) receptors. Mean frequency of spontaneous synaptic events recorded for 1015 min was 1.7 0.3 Hz (n 6) in control condition and 0.01 0.01Hz (n 5) after bath application of antagonists (P 0.05). B: firing responses of CA1 pyramidal neurons in response to a depolarizing current injection of 80pA before (top trace) and after blockade of background activity (bottom trace). Bottom: mean inputoutput relationship in control situation (C), after applicationof antagonists (A), and after washout of antagonists (W). FF denotes the firing frequency in spikes/s, which is normalized to the maximal value observed in control

condition. C: blocking background activity increased the input resistance of neurons, which partly reversed after washout of the antagonists. *P 0.05. D:plotting firing frequency against calculated membrane potential shows that as a result of the change in input resistance, the inputoutput relationship covers thesame range in membrane potential after blockade of synaptic activity; thus the change in input resistance serves to adaptively control the inputoutputrelationship. E: changes in firing frequency in response to current injections in time. Start of blockade of background activity at t 10. F: normalized restingmembrane potential (Vrest) and input resistance (Rin) in time. Solid lines indicate the mean of the 3 control time points and the dotted lines represent 2 SE ofthis mean control. Bar indicates the period of block of synaptic activity. Data points in BF represent means SE of 4 neurons.

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2009ACTIVITY-DEPENDENT ADAPTATION OF A K CONDUCTANCE



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involvement of large-conductance Ca2-activated K channels

in this sustained current component, we included Cd2 (300M) in several patches, which showed equivalent decreases inK-current amplitudes (53 9% of those in time-matchedcontrol patches after 20 min of blockade, n 4, P 0.05),suggesting that Ca2-activated K channels are not responsi-ble for the observed effect.

In addition to the sustained component of the K current, wealso analyzed the transient component of the K current, whichshowed that 20 min after blockade of activity, transient cur-rents were 80% of those in control patches (control: 95 11%,n 6; antagonists: 76 7%, n 12), a decrease that is notstatistically significant. To further determine whether the re-duction in sustained K current is adaptive in nature, we tested

K

-current amplitudes in time in cells in which only excitatorysynaptic activity was blocked. This showed an equivalentreduction in K-current amplitudes after 20 min of blockade aswith block of both excitatory and inhibitory synaptic activity(52 8% of those in time-matched control patches, n 5, P 0.05). These results indicate that the maximal conductance ofa sustained, nonCa2-activated K current is reduced withintens of minutes when background activity is blocked.

The other main determinant of membrane excitability is thevoltage-gated Na current. To test whether Na currents werealso modulated by the level of background activity, we re-corded Na currents from somatic patches in an experimentcomparable to that described for K currents. Depolarizing thesomatic membrane to potentials between 10 and 120 mV

from a 1,000-ms hyperpolarizing prepulse of 30 mV (allvoltages given are relative to resting membrane potential; seeMETHODS) resulted in fast transient inward currents (Fig. 3A).Figure 3B shows that the amplitude of the Na current tendedto decrease in time. However, the decrease in time was similarin control condition and in the presence of synaptic receptorantagonists (Fig. 3B): Na-current amplitude after 20 min of

blockade was 84% of its time-matched control (control: 85 8%, n 6; antagonists: 72 8%, n 6). For control patches,the Na conductance determined at t 30 was 52 3% of itsvalue at t 0, whereas the Na conductance at this time pointwas 46 6% of its value at t 0 (Fig. 3C). The potential ofhalf-maximal activation as well as the slope parameter werenot significantly different after blockade of background activitycompared with control (Fig. 3D). These results show thatneither the conductance nor the voltage dependency of activa-tion of Na currents is affected by blockade of backgroundactivity.

D I S C U S S I O N

In this study we investigated how background activity in thein vitro slice preparation affects the neuronal inputoutputrelationship. We show that an almost complete blockade ofbackground activity leads to an increased excitability of CA1pyramidal neurons, which is expressed as a leftward shift in theinputoutput relationship, which indicates that a given synap-tic input will evoke an increased firing rate after backgroundactivity is blocked for 1020 min. Recordings from somaticpatches showed that blockade of background activity resultedin a nearly 50% adaptive decrease in a sustained voltage-gatedK conductance with no activity-dependent changes in the

FIG. 3. Increase in excitability is not associated with a change in Na

conductance. A: Na currents from somatic patches before and after blockadeof background activity. Traces are averages of 10 consecutive sweeps. B: Na

current amplitudes normalized to its value at t 0 during either standardACSF or antagonists application (the period of application is indicated by thesolid bar). Na currents displayed some rundown in time that was equal incontrol condition and in the presence of antagonists, indicating that blockadeof background activity has no effect on Na current amplitudes. C: mean IVcurve of Na current, normalized to its value at t 0, recorded 20 min afterblockade of background activity (open symbols) or ASCF perfusion (closedsymbols). Solid lines represent the fit to the GoldmanHodgkinKatz (GHK)equation ( Eq. 3). D: voltage-dependent properties of Na currents derivedfrom the GHK fit (C) were not significantly different from those in controlpatches. Data points represent means SE of 46 cells.

FIG. 2. Reduced sustained K conductance after blockade of backgroundactivity. A: K currents in somatic patches in control condition (control) andafter blockade of activity (antagonists) in the slice. Example traces are a meanof 5 consecutive sweeps. Amplitude of the sustained K current was deter-

mined at the end of current traces (squares). Blocking background activityreduced the amplitude of K currents. Voltage is indicated as relative to restingmembrane voltage (see METHODS). B: normalized K current amplitudes beforeand during application of either standard artificial cerebrospinal fluid (ACSF)or antagonists (application period indicated by the solid bar). K-currentamplitude was normalized to its value at t 0. After 20 min of blockingactivity, K current amplitudes were 46 9% of time-matched controls. Datapoints represent means SE of 7 cells. *P 0.05. C: mean activation curvesof K currents, normalized to its value at t 0, recorded 20 min after blockadeof background activity (open symbols) or ASCF perfusion (closed symbols).Solid lines represent the fit to the Boltzmann equation ( Eq. 3). D: voltage-dependent properties of K currents derived from the Boltzmann fit (C) afterblockade of background activity were not significantly different from those incontrol patches. Data points represent means SE of 7 cells.

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voltage-gated Na conductance. Our data suggest that CA1pyramidal neurons respond to a reduction in background ac-tivity by rescaling the dynamic range of their inputoutputrelationship and that this rapid gain-setting mechanism isexpressed as an adaptive modulation of a voltage-gated sus-tained K conductance.

The somatic patch recordings of K and Na currents

suggest that the adaptive reduction in K currents is respon-sible for the increase in excitability as recorded in whole cellperforated patch mode. This reduction appeared to be the resultof a change in maximal conductance, rather than a change involtage-dependent properties of the sustained K current, al-though we cannot completely rule out the latter. Recently, itwas shown that glutamate stimulation, which mimics an in-crease in synaptic activity, results in an enhanced sustained K

current (Kv2.1) in cultured rat hippocampal neurons (Misonou

et al. 2004). Glutamate application causes a rapid dephosphor-ylation of delayed rectifier K channels, a translocation ofthese channels to the membrane and a shift in the voltage-dependent activation of the delayed rectifying current. The

change in voltage dependency of activation enhances the K

current and this effect was already apparent after 10 min ofglutamate stimulation. The observations of Misonou et al.describe a functional upregulation of the delayed rectifier as aresult of glutamate application that is complementary to ourcondition of reduced background activity. However, we did notdetect a significant change in voltage-dependent properties ofthe sustained K conductance, but a large decrease in maximalconductance, suggesting that the underlying molecular mech-anisms may be different. Because of the similarity in timescaleon which these two different mechanisms operate, however,they could be complementary mechanisms in the activity-dependent dynamic control of neuronal excitability.

Several studies have shown that voltage-gated conductances

can be modulated in an adaptive or homeostatic manner bysynaptic activity. Most of these mechanisms were found tooccur after long-term modulation of activity of hours to days(Aptowicz et al. 2004; Baines et al. 2001; Desai et al. 1999;Golowasch et al. 1999; Turrigiano et al. 1995), although morerecent studies have shown that adaptive modulation of voltage-gated conductances can also occur on a timescale of minutes(Baines et al. 2003; Misonou et al. 2004; Nelson et al. 2003;van Welie et al. 2004). The fact that several mechanisms havenow been observed at different timescales suggests the exis-tence of a range of different underlying molecular mechanismsthat may include modulation of ion channel density by eithertranscriptional or translational regulation as well as modulation

of ion channel function by posttranslational mechanisms suchas phosphorylation or dephosphorylation. It will be importantto investigate how these modulatory mechanisms relate to thelevels and duration of changes in activity. One study reportedactivity-dependent changes in Na- and K-channel conduc-tances that occurred only after modulating activity for 24 h(Desai et al. 1999). In that study, activity was blocked incultured neocortical neurons, which resulted in an increase inexcitability that was correlated to an increase in Na conduc-tance and a decrease in persistent K conductance. The down-regulation in sustained K current we find is equivalent to theresults from Desai et al. (1999), although we did not see anincrease in Na conductance and the increase in excitabilitywe report is already apparent after 1020 min. Desai et al.

(1999), however, did not investigate time points 2.5 h. Also,activity was blocked by blocking postsynaptic receptors in ourexperiments, whereas in the study of Desai et al. (1999)activity was blocked at the presynaptic side, which might haveimportant implications for the mechanisms induced. Thesedifferences might indicate that sustained K conductances canbe regulated at different timescales by a variety of underlying

molecular mechanisms.In summary, we have shown that CA1 pyramidal neurons in

the in vitro slice preparation dynamically adapt their inputoutput relationship in response to blockade of backgroundactivity by scaling a voltage-gated K conductance. Thismechanism may act in concert with the previously proposedgain-setting roles of background activity (Chance et al. 2002;Fellous et al. 2003; Shu et al. 2003). We conclude thatregulation of neuronal excitability is a highly dynamical pro-cess and that voltage-gated channels are subject to activity-dependent adaptive modulation at shorter timescales than pre-viously assumed.

A C K N O W L E D G M E N T S

Present address of I. van Welie: Systems Neurobiology Laboratories, TheSalk Institute for Biological Studies, La Jolla, CA 92037.

G R A N T S

This work was supported by a fellowship of the Royal NetherlandsAcademy of Arts and Sciences to J. A. van Hooft.

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