Homeostatic shutdown of long-term potentiationin the adult hippocampusClaudia Roth-Alpermann*, Richard G. M. Morris†, Martin Korte*‡, and Tobias Bonhoeffer*§

*Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany; and †Laboratory for Cognitive Neuroscience,University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, United Kingdom

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA, and approved June 5, 2006 (received for review February 6, 2006)

Homeostasis is a key concept in biology. It enables ecosystems,organisms, organs, and cells to adjust their operating range tovalues that ensure optimal performance. Homeostatic regulationof the strength of neuronal connections has been shown to play animportant role in the development of the nervous system. Here weinvestigate whether mature neurons also possess mechanisms toprevent the strengthening of input synapses once the limit of theiroperating range has been reached. Using electrophysiologicalrecordings in hippocampal slices, we show that such a mechanismexists but comes into play only after a considerable number ofsynapses have been potentiated. Thus, adult neurons can sustaina substantial amount of synaptic strengthening but, once a certainthreshold of potentiation is exceeded, homeostatic regulationensures that no further strengthening can occur.

homeostasis � synaptic plasticity � metaplasticity

Neurons possess a variety of mechanisms for homeostaticregulation of ion concentrations, osmotic conditions, oxy-

gen consumption, and other metabolic processes. However,neurons not only have to monitor and control basic metabolicparameters but also have to regulate neural activity carefully.Homeostatic compensatory mechanisms are well documentedduring the development of the nervous system (1, 2). Suchmechanisms should remain important after functional synapticconnections are established and neuronal circuits have attaineda mature state, because the adult nervous system continuouslyneeds to adapt to environmental changes.

The cellular underpinnings of learning and memory includemechanisms that alter the efficacy of synaptic connections (3, 4).Such mechanisms, although necessary for the storage of infor-mation, run the risk of strengthening the inputs to an individualneuron to an extent that it, or an entire neuronal network, movesbeyond their optimal operating range. To ensure proper func-tioning, neural networks have to balance two seemingly con-flicting requirements: change and stability. A dynamic equilib-rium between these opposing but complementary processes isespecially important in a highly plastic brain structure, such asthe hippocampus, that has been implicated in different forms ofmemory (5, 6).

Hebb’s postulate of activity-dependent synaptic plasticity (7)was experimentally confirmed with the discovery of long-termpotentiation (LTP) in the hippocampus (8). Subsequent workhas posited that, to ensure stability of the neuronal network, thisvery ability of neurons to undergo changes in synaptic strengthshould itself be subject to activity-dependent regulation (9), asnow experimentally demonstrated with the phenomenon of‘‘metaplasticity’’ (10). Metaplasticity is a form of homeostasis inwhich the history of previous neuronal activation influences thedirection and degree of synaptic plasticity elicited by a givenstimulus.

Hippocampal pyramidal cells of the CA1 region each receivethousands of excitatory inputs with the potential for activity-dependent increases in synaptic efficacy (11). Without mecha-nisms for limiting total synaptic strength, their physiologicalbalance might be compromised and, if too many of their inputs

were potentiated, selective differences in synaptic weights woulddiminish, reducing the information-storage capacity of neuronalcircuits (12, 13). We therefore hypothesized that CA1 neuronsmight possess homeostatic mechanisms to regulate total synapticstrength. We set out to investigate whether saturating potenti-ation in one set of CA1 hippocampal synapses might diminish oreven prevent further potentiation of a different set of synapseson the same neurons. Because it is unclear what proportion ofsynapses must be potentiated before homeostatic regulationcomes into play, we considered both electrical tetanization of theSchaffer collateral input to area CA1 and a chemical potentia-tion procedure that activates a high proportion of excitatoryafferents throughout CA1. Although this might be perceived asmore ‘‘artificial,’’ chemical potentiation utilizes induction mech-anisms similar to that of electrical tetanization (see, e.g., refs.14–17) and critically should realize the maximal potentiationthat individual neurons can sustain. Our series of extra- andintracellular experiments demonstrate that synaptic activationcan cause a heterosynaptic shut down of LTP, but the operatingrange of hippocampal neurons appears to be exceptionallybroad.

ResultsProbing Homeostasis on a Population of Neurons: Normal LTP DespiteSaturation of Synaptic Inputs. The experiments were performed inrat hippocampal slices by using classical NMDA-receptor-dependent CA3–CA1 LTP. Field excitatory postsynaptic poten-tials (fEPSPs) were measured in the stratum radiatum of theCA1 region, whereas stimuli were elicited in two independentpathways (see Methods and Supporting Text, which is publishedas supporting information on the PNAS web site). Multipletetanizations of one pathway were applied to induce saturatedLTP, with saturation operationally defined as the inability toinduce further LTP on the same pathway with the same tetanus(saturated pathway, 156 � 6% 1 hr and 144 � 9% 6 hr after thelast tetanus, n � 12, Fig. 1a). The second, or test, pathway wasmonitored continuously to ensure that it experienced no LTPwhen the saturated pathway was tetanized. One hour later, thetest pathway was probed for its ability to undergo LTP. Theclassical principle of input specificity indicates that induction ofLTP on one pathway is independent of that on another. But ifa homeostatic mechanism were to limit the total amount ofpotentiation, prior saturation might block or at least reduce LTPin the other subset of synapses. We found no evidence for thisassumption. Robust LTP was observed in the test pathway of amagnitude no smaller than that seen in control slices withoutprevious saturation (LTP in test pathway, 138 � 5%; LTP in

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: LTP, long-term potentiation; fEPSP, field excitatory postsynaptic potential.

‡Present address: Zoological Institute, Technische Universitat Braunschweig, Men-delssohnstrasse 4, 38106 Braunschweig, Germany.

§To whom correspondence should be addressed. E-mail: tobias.bonhoeffer@neuro.mpg.de.

© 2006 by The National Academy of Sciences of the USA

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control slices, 136 � 6%; both 1 hr after LTP induction, P � 0.10;Fig. 1 a and b). Long-term recordings showed that late LTP wasalso unaffected by the earlier saturating stimulus (6 hr after

tetanus: 122 � 6% in the test pathway, 121 � 7% in the controlslices, P � 0.10; Fig. 1b).

At first glance, these observations argue against homeostatic

Fig. 1. Saturation of one pathway did not block or reduce LTP in another independent pathway. (a) Multiple tetanization (open arrows) of one Schaffer collateralpathway induced saturated and long-lasting LTP (saturated pathway, 156 � 6% 1 hr and 144 � 9% 6 hr after the last tetanus, n � 12). One hour later, a secondindependent pathway in the same slice (test pathway) received a single tetanus (filled arrow) to probe its capability to undergo LTP. The test pathway showed robustlong-lasting LTP as well (138 � 5% 1 hr and 122 � 6% 6 hr after LTP induction, n � 12). (b) The amount of LTP in the test pathway did not differ from LTP observedin control slices without previous saturation (136 � 6% 1 hr and 121 � 7% 6 hr after LTP induction, n � 10, P � 0.10). Arrow, tetanus to the test pathway or to controlslices. (c) Example of an intracellular saturation experiment. Open arrows, tetani to the saturated pathway; filled arrow, tetanus to the test pathway. For the plot,amplitudes of two consecutive EPSPs were averaged; action potentials are indicated by vertical bars. (a–c) Representative fEPSPs were taken before and after LTPinduction at the time points indicated in the graphs (averaged over five consecutive sweeps). Error bars indicate � SEM. (d) Correlation analysis for eight intracellularsaturation experiments. The amount of LTP in the saturated pathway is plotted against the amount of potentiation in the test pathway 1 hr after the (last) tetanus.The homeostatic hypothesis predicts a negative correlation, but this was not observed (correlation coefficient r2 � 0.08, P � 0.49).

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regulation of synaptic efficacy, but they are not fully conclusive.One reason is that the populations of CA1 neurons stimulatedby the two pathways might not be sufficiently congruent. Manyneurons will receive input from both pathways (these are theneurons of interest), but there might also be neurons that receiveinput from the test pathway only. These would, of course, exhibitnormal LTP in response to the test tetanus. Their contributionto the fEPSPs might therefore mask a potential homeostaticeffect. We therefore performed a second series of experiments,recording from individual CA1 neurons with sharp intracellularelectrodes.

Probing Homeostasis on a Single Neuron: Normal LTP Despite Satu-ration of Synaptic Inputs. The experimental stimulating protocolwas very similar to that used for the extracellular recordings (seeSupporting Text). We found that again, despite robust LTP on thesaturated pathway (151 � 8%, 1 hr after the tetanus, n � 8),single CA1 neurons could still exhibit additional potentiation inresponse to a tetanus in the test pathway (124 � 7%, 1 hr afterthe tetanus, n � 8; see example in Fig. 1c), arguing against ahomeostatic effect. Moreover, correlation analysis did not reveala negative correlation between the magnitude of LTP in thesaturated and test pathways (Fig. 1d; correlation coefficient r2 �0.08, P � 0.49); if anything, there was a trend for a positivecorrelation (r2 � 0.87, P � 0.01, n � 6, with two outliersremoved), again arguing against a homeostatic effect.

The result led us to ask whether the saturation of one pathwayis quite the same as the induction of LTP at a high proportionof a neuron’s afferents. As Moser et al. (12) have noted in vivo,it may be that the total number of potentiated synapses remainwithin the working range after tetanization of a single pathway,and thus below the threshold required to trigger homeostasis.

Homeostatic Control of LTP After Widespread Synaptic Strengthening.Chemical LTP is an alternative induction protocol that shouldresult in a much larger proportion of synapses on individualneurons being potentiated. We used a brief bath application ofa potentiation medium containing increased potassium, reducedmagnesium, and 25 mM of the potassium-channel blockertetraethylammonium (refs. 14 and 18; see Supporting Text). Theinduced LTP was similar to electrical LTP with respect toduration, pharmacology, and mutual occlusion (see Fig. 4, whichis published as supporting information on the PNAS web site; seealso refs. 15–17).

To induce chemical LTP in a high proportion, but not in all,of a neuron’s afferents, a local superfusion technique (19) wasused to protect a small group of synapses from the potentiationmedium (Fig. 2; Fig. 5, which is published as supporting infor-mation on the PNAS web site). The superfusion medium wassimilar to the normal recording solution but contained a highercalcium concentration (10 mM). To isolate the synapses withinthe superfusion spot pharmacologically, synaptic transmissionoutside the superfusion spot could be blocked by replacing thenormal extracellular medium with a solution containing reducedcalcium (1.2 mM) and low cadmium (5 �M).

The sequence of steps was as follows. Throughout the exper-iment, baseline stimulation was performed by a stimulatingelectrode in the Schaffer collaterals; by using an electrode whosetip was positioned in the superfusion spot, fEPSPs were recordedin the stratum radiatum of the CA1 region. During an initialperiod in which synaptic transmission was enabled within thesuperfusion spot while it was blocked in the rest of the slice, thepositions of the stimulating electrode, the superfusion spot, andthe recording electrode were adjusted to achieve an optimalpostsynaptic response. After changing the blocking solution backto normal medium, the signal recovered (first 50–100 min of theexperiments; data not displayed in Fig. 2). The chemical poten-tiation medium was then bath-applied for 10 min to induce LTP

throughout the slice except at those synapses in the superfusionspot (Fig. 2a; approximately �100 to �90 min). Chemical LTPwas monitored for 1 hr, and the blocking solution then washedin again for the outside-spot synapses, effectively isolating thesynapses within the spot. This decreased the fEPSP amplitude,because the outside-spot fraction of synapses was silenced,resulting in a signal that reflected only the strength of theinside-spot synapses (Fig. 2a, from around �30 min on). In thedecisive last phase of the experiment (shaded part of Fig. 2 a andc), these test synapses were then probed with an electrical LTPstimulus for their ability to undergo potentiation. After record-ing a stable baseline, a tetanus was applied to the inside-spotsynapses. Fig. 2c (light-blue symbols) that displays only this lastphase shows that LTP at these synapses did not occur (testexperiments, 98 � 3%, 1 hr after tetanus, n � 6). To check thatthis lack of LTP was not a trivial consequence of failing to reachthe cooperativity threshold for LTP induction (20) within thesmall population of inside-spot synapses, control experimentswere performed according to the same protocol but withoutchemical potentiation. These showed normal LTP (Fig. 2 b andc, dark-blue symbols; control experiments, 136 � 11%, 1 hr aftertetanus, n � 5, P � 0.05).

However, comparison of the signal amplitudes during the firstand second blocking periods revealed an unexpected increase ofthe inside-spot fEPSP after chemical LTP induction outside(145 � 8%, n � 8; data not shown), indicating that potentiatingmedium might have leaked into the superfusion spot, therebypotentiating some synapses at the border. Apparent LTP shut-down might then be no more than homosynaptic occlusion (as inFig. 4c) rather than heterosynaptic homeostasis. We thereforerepeated the entire experiment under circumstances in which theinduction of LTP in the spot was pharmacologically prevented(Fig. 2 d–f ). Chemical LTP can be completely blocked by theNMDA-receptor antagonist AP5 together with the L-type cal-cium channel blocker verapamil (100 and 30 �M, respectively;Fig. 3; see also Supporting Text). AP5 and verapamil weretherefore added to the superfusion medium 20 min before andduring and until 40 min after the potentiation medium wasapplied to the outside-spot synapses. No increase of fEPSPamplitude occurred from the first to the second blocking period(87 � 10%, n � 6; data not shown). We still observed that thetest synapses failed to undergo LTP after the outside-spotsynapses had been potentiated chemically (100 � 7%, n � 6),whereas, under control conditions (without potentiation of theoutside-spot synapses), normal LTP occurred (124 � 8%, n � 6).This difference was statistically significant (P � 0.05, 1 hr aftertetanus; Fig. 2f ). This second series of superfusion experiments,performed under strict pharmacological control, confirmed theobservation of homeostatic shutdown after widespread synapticstrengthening.

Numerous studies performed by others (e.g., refs. 14–17), aswell as our own experiments (see Fig. 4), indicate that electricaland chemical LTP are similar. To rule out that an additionalunspecific effect of the potentiation medium may have causedthe shutdown of LTP, we performed a control in which weinverted the experimental logic: AP5 and verapamil were nowboth added to the potentiation medium. This should block theinduction of chemical LTP and, therefore later electrical LTPshould still occur in normal extracellular recordings withoutsuperfusion. Adding AP5 (100 �M) and verapamil (30 �M) tothe potentiation medium blocked chemical LTP (107 � 5% 1 hrafter LTP induction, n � 7; Fig. 3). As predicted, after thewashout of AP5 and verapamil, electrically induced LTP couldstill occur (131 � 5% 1 hr after tetanus, n � 7). This demon-strates that the lack of LTP in the inside-spot synapses cannot beexplained by the potentiation solution causing harm to the cellsor interfering with fundamental physiological parameters.

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Fig. 2. Homeostatic control of LTP after widespread synaptic strengthening. A large proportion of synapses were potentiated by inducing chemical LTPthroughout the slice except within a superfusion spot. The superfused and therefore unpotentiated synapses were then probed for their capability to expressLTP. (a and b) Experimental design and representative example of a test (a) and control experiment (b). Inside- and outside-spot synapses are synapses in or outsidethe superfusion spot. BLOCK, bath application of blocking medium; POT, bath application of potentiation medium. Blocking and potentiation medium haveaccess to the outside- but not the inside-spot synapses. A tetanus was applied at time point zero (arrow). (c) Population data show no LTP could be induced afterwidespread synaptic strengthening (test experiments: 98 � 3% 1 hr after tetanus, n � 6), but normal LTP was expressed (control experiments, 136 � 11% 1 hrafter tetanus, n � 5) without prior chemical LTP. The difference between control and test experiments is significant (P � 0.05). Not all of the eight test and eightcontrol experiments lasted until 1 hr after tetanus. Shaded area in c corresponds to shaded areas in a and b. Error bars indicate � SEM. (d–f ) Same as a–c, butAP5 (100 �M) and verapamil (30 �M) were present in the superfusion solution 20 min before, during, and 40 min after the bath application of potentiationmedium to prevent undesired potentiation of the superfused synapses. Open arrowheads, transient depressions in fEPSP amplitude due to the exchange of thesuperfusions solutions (see Supporting Text). This second series of superfusion experiments with pharmacological protection of the superfusion spot confirmedthe observation of homeostatic shutdown of LTP; no LTP after widespread synaptic strengthening (test experiments, 100 � 7% 1 hr after tetanus, n � 6) andnormal LTP in control experiments (124 � 8% 1 hr after tetanus, n � 6). The difference between test and control experiments is significant (P � 0.05).Representative fEPSPs averaged from five consecutive stimuli were taken at the time points specified in the graph.

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DiscussionOur data show that widespread synaptic strengthening by chem-ical means results in a shutdown of LTP. Homeostatic regulationof LTP was not observed after conventional electrical potenti-ation from a single stimulating electrode. Given that bothelectrical and chemical forms of LTP target the same subcellularmachinery (Fig. 4 and refs. 14–17), it is most likely that theimportant difference between these methods of potentiation liesin the proportion of synapses that are strengthened, rather thanin the induction mechanism per se. CA1 cells are contacted byonly few terminals from each afferent CA3 cell (21, 22). Ac-cordingly, it may not be feasible, within a hippocampal slice, toactivate a sufficiently high proportion of afferents onto anindividual cell with electrical stimulation from a single stimula-tion electrode. In contrast, chemical potentiation ensures wide-spread activation of the population of available synapses in aslice. We estimate that �90% of recorded CA1 synapses were incontact with the chemical potentiation medium, but it is unlikelythat all of these activated synapses were successfully potentiated(see Supporting Text; see also ref. 11). The threshold for homeo-static control of LTP may therefore be considerably lower thanthe 90% of synapses activated, but our experiments were notgeared to determine the minimal number of potentiated syn-apses necessary.

One might argue that chemical LTP is a highly unphysiologicalway to induce synaptic potentiation. However, both the electricaland chemical forms of inducing LTP are in vitro stimulationprotocols that are unphysiological in comparison to the in vivosituation. Because an individual CA1 cell has up to 30,000excitatory synapses (23) and receives inputs from a very largenumber of CA3 cells (21), it is not unreasonable to suppose thatcircumstances may arise quite frequently in individual neuronsin which the operating range (i.e., total sustainable synapticefficacy) of a CA1 cell is approached or even reached. Thus, thedynamic effects of chemical potentiation may, at least in singlecells, be more realistic than they may seem initially. In vivorecordings in the hippocampus of behaving rats and monkeysshow that a high proportion of the recorded neurons changetheir activity in response to the respective learning task: in a

spatial navigation task, 75% of neurons in the hippocampal CA1region were found to have a place field (24); in an odor-guidednonmatching-to-sample task, the activity of 72% of CA1 andCA3 neurons was associated with one or more of the variablestested (25); in a location-scene association task, 61% of therecorded hippocampal cells responded in a scene-selective fash-ion (26). These examples support the idea that hippocampal CA1neurons in vivo may experience widespread synaptic input as thehippocampus processes information, and widespread synapticstrengthening might be not such an uncommon event. Asmeasured by using the molecular tagging of AMPA receptors, asmany as 30% of amygdala neurons actually undergo synapticplasticity in an associative learning task (27). That a simplelearning paradigm such as tone-shock pairing induces wide-spread plasticity makes it plausible to assume that the complexdaily demands upon an animal could result in a similar (or evenlarger) proportion of neurons in the hippocampus being subjectto extensive potentiation.

Still, the capacity of the brain is limited. The critical numberof potentiated synapses may be reached under some circum-stances in individual neurons, such that further synapticstrengthening has to be shut down to prevent ‘‘catastrophicinterference’’ in neural networks (28) and to preserve informa-tion already stored (13, 29, 30). Our findings demonstratinghomeostatic control of LTP complement and extend earlier invivo studies that tested the proposed link between LTP andlearning (for review, see refs. 4 and 31). Rioult-Pedotti et al. (32)observed that prior skill learning uses an LTP-like mechanism inthe motor cortex that strongly diminishes the capacity for furthersynaptic enhancement. Saturation of LTP in the hippocampuscan similarly prevent both further LTP and hippocampus-dependent spatial learning (12, 33). These in vivo studies did notattempt to distinguish between homosynaptic occlusion andheterosynaptic homeostasis, but they strengthen the notion thatsituations may indeed be experienced where learning-inducedplasticity drives a neuronal circuit to its limits, resulting in ashutdown of plasticity.

The shutdown of LTP belongs to a family of homeostaticprocesses that act in the nervous system to maintain the stabilityof neuronal function under ever-changing conditions. There aredifferences in the timing, target, and trigger of the respectiveregulatory strategy. In the amygdala, for instance, activity-dependent potentiation of some inputs leads to immediatedepression at different synaptic sites on the same neuron andvice versa, thus keeping the net change of synaptic weightsroughly balanced (34). In the hippocampal area CA1, heterosyn-aptic depression is sometimes, but not always, observed (35, 36).Here we did not observe heterosynaptic depression in thesuperfusion spot after widespread potentiation.

The homeostatic regulation of LTP we describe here is distinctfrom synaptic scaling (37) and from competitive maintenance ofLTP (38). These phenomena both consist of a direct regulationof synaptic strength after global modulation of synaptic activity(synaptic scaling) or local potentiation of synaptic inputs (com-petitive maintenance). Compared to the former case, the ho-meostatic mechanism we report operates by preventing addi-tional potentiation: synaptic strength per se is not affected.Compared to the latter, induction of additional potentiationresults in the decrease of prior LTP at different synapses.Competitive maintenance is observed under conditions wherethe levels of plasticity proteins are low (during protein synthesisinhibition or after weak LTP induction). Shutdown of LTP, incontrast, occurs after widespread potentiation, a plasticity re-gime where a competitive maintenance effect is not to beexpected.

Homeostatic shutdown of LTP does relate to the Bienen-stock–Cooper–Munro (BCM) theory (9) and the concept ofmetaplasticity (10, 39). The BCM model proposes that experi-

Fig. 3. Shutdown of LTP is not due to unspecific effects of the potentiationmedium. Chemical LTP is blocked by AP5 (100 �M) and verapamil (30 �M,107 � 5% 1 hr after LTP induction). After the washout of these drugs, LTP couldbe induced normally by a tetanus (131 � 5% 1 hr after tetanus, n � 7). AP5 andverapamil were present in the extracellular medium 20 min before and duringand 40 min after the bath application of potentiation medium. The timing ofthe experiment (delay between chemical LTP and electrical LTP) and theconcentrations of the drugs were precisely the same as in the original super-fusion experiments. Representative fEPSPs averaged from five consecutivestimuli were taken at the time points specified in the graph. Arrow, tetanus.Error bars indicate � SEM.

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ence-dependent plasticity is regulated by the prior history ofneuronal activation, as shown in visual cortex and hippocampus(40, 41). Metaplasticity in the most general sense includes shiftsof the modification threshold for LTP (42).

Interpreting our data from the angle of metaplasticity, onecould argue that the shutdown of LTP may be explained by aradical right-shift of the Bienenstock–Cooper–Munro (BCM)curve above the LTP threshold. Although we cannot completelyexclude this interpretation, we find it unlikely, because it wouldimply that, after widespread strengthening, the curve would shiftsuch that the 100-Hz tetanus used to probe for LTP wouldexactly correspond to the zero crossing of the curve (i.e., theLTD�LTP modification threshold). None of the earlier studiesthat parametrically tested the possible shifts of the BCM curvehave given any evidence that the modification threshold can beas high as 100 Hz, finding only values between 3 and 30 Hz (43).

What are the potential mechanisms underlying the shutdownof LTP? This is a matter for future work, but the possibilities fallinto two broad categories: resource depletion or active homeo-static regulation. A passive resource depletion model wouldinvolve chemical LTP using up limited resources necessary forLTP induction [e.g., AMPA receptors (27) or neurotrophins]. Incontrast, direct homeostatic regulation could operate on anetwork level (e.g., by increasing inhibition) or at the level of anindividual neuron. For example, a reduction in excitabilityaffecting the whole neuron might make subsequent potentiationharder (44–47). In contrast to resource depletion, the attractivefeature of regulation is that the system might be activated inother circumstances, such as the induction of stress or otherconditions in which potentiation should be stopped (48).

Our findings indicate that widespread synaptic strengtheningon a population of neurons can prevent further potentiation oftheir inputs, but this homeostatic shutdown is not ordinarilyobserved by using conventional stimulation techniques. Bothresults are telling, because they reflect two faces of the samecoin. On the one hand, neurons can be quite robust, allow theirsynaptic population to regulate their efficacy relatively indepen-dently, and thus sustain a substantial increase in total synapticweight. On the other hand, neurons seem to have evolvedstrategies of coping with excess synaptic drive. These include, aswe have shown, the homeostatic control of LTP.

MethodsAcute hippocampal slices were prepared from male Wistar rats(4–6 weeks old), following standard procedures. Stimulationelectrodes were positioned in the Schaffer collateral axons ofarea CA3; the responses elicited in CA1 pyramidal neurons wererecorded either extracellularly or intracellularly. LTP was in-duced by high-frequency stimulation (tetanus: 100 Hz, 100pulses) or by chemical potentiation (14). The local superfusiontechnique had been described in detail (19). Data are presentedas mean � SEM. Two-tailed Student’s t tests were used toanalyze differences in physiological parameters. The criticalvalue was set at P � 0.05.

Detailed methods are published in Supporting Text.

We thank Volker Staiger for his outstanding technical assistance andAlexander Borst, Mark Hubener, and Christian Lohmann for helpfuldiscussions and comments on the manuscript. This work was supportedby the Max Planck Society (C.R.-A., M.K., and T.B.), a HeisenbergStipend of the Deutsche Forschungsgemeinschaft (to M.K.), and theUnited Kingdom Medical Research Council (R.G.M.M.).

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