Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.

We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].     

Separate mechanisms of long-term potentiation in two input systems to CA3 pyramidal neurons of rat hippocampal slices as revealed by the whole-cell patch-clamp technique.

Excitatory synaptic transmission from two input systems to hippocampal CA3 pyramidal neurons was investigated by the whole-cell patch-clamp technique for thin slice preparation, with special reference to long-term potentiation (LTP) in these systems. Excitatory postsynaptic currents (EPSCs) evoked by fimbrial stimulation consisted of two components; one was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the other was persistent at depolarized membrane potentials and blocked by D-2-amino-5-phosphonovalerate (D-AP5). The contribution of the D-AP5-sensitive component to EPSCs evoked by stimulation of mossy fibers was much less than that to fimbrial EPSCs. High-frequency stimulation of afferent fibers, under current-clamp conditions, elicited LTP. Bath application of D-AP5 blocked the induction of LTP in the fimbrial but not in the mossy fiber synapses. Induction of fimbrial LTP was completely blocked by 10 mM BAPTA applied intracellularly. In contrast, mossy fiber LTP was not blocked by 10 mM BAPTA. Furthermore, mossy fiber LTP, but not fimbrial LTP, was elicited by high-frequency stimulation under voltage-clamp (-80 mV) conditions. These results suggest that activation of NMDA receptors, increase in postsynaptic [Ca2+]i, and postsynaptic membrane depolarization are required for the induction of fimbrial but not for mossy fiber LTP.     

Enhancement of postsynaptic responsiveness during long-term potentiation of mossy fiber synapses in guinea pig hippocampus.

The primary site responsible for the long-lasting enhancement of synaptic transmission during long-term potentiation (LTP) was examined by quantal analysis of excitatory postsynaptic potentials in thin sections of the guinea pig hippocampus. With induction of LTP in mossy fiber synapses, estimated values of quantal amplitude (q) and Pascal parameters p and r were increased significantly. No increases in quantal content (m) were detected. The magnitude of increases in q was almost equal to that of LTP. These results indicate that LTP in mossy fiber synapses results from increases in responsiveness of postsynaptic neurons.     

Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.     

Mossy fiber long-term potentiation shows specificity but no apparent cooperativity.

Specificity in long-term potentiation (LTP) means that synapses onto a postsynaptic cell can potentiate independently of one another. Cooperativity refers to a requirement that some threshold number of afferents be co-activated to evoke LTP with a high-frequency stimulus. The induction of long-term potentiation (LTP) at the associational/commissural synapses onto hippocampal CA3 pyramidal cells shows clear cooperativity. LTP of mossy fiber inputs to these cells does not. Mossy fiber LTP does show synapse specificity. These results bear on the cellular mechanisms and the functions of mossy fiber LTP.     

Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists

Receptors preferentially activated by the excitatory amino acid N-methyl-D-aspartate (NMDA) do not mediate synaptic transmission in the hippocampus but are involved in initiating long-term potentiation (LTP) in hippocampal region CA1. We have examined the role of NMDA receptors in LTP of the commissural/associational and mossy fiber pathways to region CA3 pyramidal neurons. In the commissural/associational pathway, NMDA receptor blockers did not reduce synaptic responses but reversibly blocked the induction of LTP. In contrast, NMDA receptor blockers had no effect on mossy fiber LTP. These results suggest that induction of commissural/associational LTP differs from mossy fiber LTP, although the mechanisms underlying expression of LTP along these pathways could be similar. Kynurenate and L-2-amino-4-phosphonobutyrate, which potently reduce mossy fiber responses, also did not block induction of mossy fiber LTP.     

Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum

Various forms of synaptic plasticity underlying motor learning have already been well characterized at cerebellar parallel fibre (PF)–Purkinje cell (PC) synapses. Inhibitory interneurones play an important role in controlling the excitability and synchronization of PCs. We have therefore tested the possibility that excitatory synapses between PFs and stellate cells (SCs) are also able to exhibit long-term changes in synaptic efficacy. In the present study, we show that long-term potentiation (LTP) and long-term depression (LTD) were induced at these synapses by a low frequency stimulation protocol (2 Hz for 60 s) and that pairing this low frequency stimulation protocol with postsynaptic depolarization induced a marked shift of synaptic plasticity in favour of LTP. This LTP was cAMP independent, but required nitric oxide (NO) production from pre- and/or postsynaptic elements, depending on the stimulation or pairing protocol used, respectively. In contrast, LTD was not dependent on NO production but it required activation of postsynaptic group II and possibly of group I metabotropic glutamate receptors. Finally, stimulation of PFs at 8 Hz for 15 s also induced LTP at PF–SC synapses. But in this case, LTP was cAMP dependent, as was also observed at PF–PC synapses for presynaptic LTP induced in the same conditions. Thus, long-term changes in synaptic efficacy can be accomplished by PF–SCs synapses as well as by PF–PC synapses, suggesting that both types of plasticity might co-operate during cerebellar motor learning.     

NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses

Hippocampal mossy fiber synapses have been reported to lack NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA excitatory postsynaptic currents (EPSCs), unlike conventional glutamatergic synapses. An explanation for this difference may reside in the relatively low number of NMDARs at these synapses. Because mossy fiber synapses display LTP selective for NMDARs, we examined whether this would affect the plasticity rules at mossy fiber-CA3 synapses in mouse hippocampal slices. We found that LTP of NMDARs serves as a metaplastic switch making mossy fiber synapses competent for generating NMDAR-dependent LTP of AMPA EPSCs.     

Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation

Hippocampal mossy fiber synapses show an unusual form of long-term potentiation (LTP) that is independent of NMDA receptor activation and is expressed presynaptically. Using receptor antagonists, as well as receptor knockout mice, we found that presynaptic kainate receptors facilitate the induction of mossy fiber long-term potentiation (LTP), although they are not required for this form of LTP. Most importantly, these receptors impart an associativity to mossy fiber LTP such that activity in neighboring mossy fiber synapses, or even associational/commissural synapses, influences the threshold for inducing mossy fiber LTP. Such a mechanism greatly increases the computational power of this form of plasticity.     

In vivo BDNF modulation of adult functional and morphological synaptic plasticity at hippocampal mossy fibers

Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.     

Local protein synthesis and GABAB receptors regulate the reversibility of long-term potentiation at murine hippocampal mossy fibre–CA3 synapses

Reversal of long-term potentiation (LTP) by long trains of low-frequency stimulation is generally referred to as depotentiation. One of the intriguing aspects of depotentiation is that the magnitude of depotentiation is inversely proportional to the time lag of depotentiation stimulation following LTP induction. Although the mechanisms underlying depotentiation have been widely explored, the factors that regulate the susceptibility of LTP to depotentiation stimulation remain largely unclear. We now report that multiple trains of high-frequency stimulation provide immediate synaptic resistance to depotentiation stimulation at the mossy fibre–CA3 synapses. The synaptic resistance to depotentiation stimulation depends on the amount of synaptic stimulation used to induce LTP; it is prevented by protein synthesis inhibitors and is input specific. In contrast, neither the transection of mossy fibre axons near granule cell somata nor the application of RNA synthesis inhibitors influences synaptic resistance to depotentiation stimulation. We also provide evidence that the induction of depotentiation is regulated by GABA_B receptors. Application of a GABA_B receptor antagonist significantly promoted the synaptic resistance to depotentiation stimulation, whereas inhibition of GABA transport delayed the onset of this synaptic resistance. These results suggest that local protein synthesis is required for the development of synaptic resistance to depotentiation stimulation, whereas the activation of GABA_B receptors promotes the susceptibility to depotentiation stimulation. These two factors may crucially regulate the reversal and stability of long-term information storage.     

Induction of long-term potentiation at hippocampal mossy-fiber synapses follows a Hebbian rule

1. The induction of long-term potentiation (LTP) at hippocampal mossy-fiber synapses requires an increase in postsynaptic [Ca2+]i but is independent of N-methyl-D-aspartate (NMDA) receptor activation. Voltage-gated Ca2+ channels have been proposed as one alternative source for raising [Ca2+]i during the induction of LTP. We tested the hypothesis that voltage-gated Ca2+ channel activation could mediate the induction of LTP by examining whether 1) the induction of mossy-fiber LTP was dependent on postsynaptic depolarization and 2) depolarization alone, of a magnitude presumably capable of activating Ca2+ channels, was sufficient to induce LTP. 2. Intracellular recordings were made from rat CA3 pyramidal cells in the hippocampal slice preparation under both current- and voltage-clamp conditions. Mossy-fiber postsynaptic potentials and currents were recorded before and after high-frequency stimulation (HFS) in the presence of 20-50 microM D-2-amino-5-phosphonovaleric acid (D-APV), an NMDA-receptor antagonist. 3. Voltage clamping of CA3 neurons between -80 and -100 mV during HFS reversibly blocked the induction of mossy-fiber LTP. Conversely, HFS paired with depolarizing-current steps under current clamp increased the magnitude of LTP compared with controls. These results indicate that mossy-fiber LTP is dependent on postsynaptic depolarization, and presynaptic activation alone was not sufficient to induce mossy-fiber LTP. 4. Depolarizing-current injections, which presumably depolarized CA3 cells to potentials sufficient to activate voltage-gated Ca2+ channels, had no effect on mossy-fiber synaptic responses. These results suggest that synaptic activation, in addition to postsynaptic depolarization, is required for the induction of mossy-fiber LTP. 5. Single mossy-fiber afferent volleys were also paired with depolarizing-current pulses. In the presence of APV, pairing of single-mossy-fiber excitatory postsynaptic potentials (EPSPs) with postsynaptic depolarization did not potentiate synaptic responses, suggesting that some form of HFS is also required for mossy-fiber LTP. In the absence of APV, however, the contamination of mossy-fiber synaptic responses by CA3-recurrent inputs resulted in some potentiation. 6. These results suggest that the induction of mossy-fiber LTP is dependent on both pre- and postsynaptic activity and thus follows a Hebbian rule for synaptic modification. In contrast to that demonstrated at Schaffer-collateral-commissural synapses, however, the induction of mossy-fiber LTP may require HFS in addition to postsynaptic depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)     

NO enhances presynaptic currents during cerebellar mossy fiber-granule cell LTP

Nitric oxide (NO) is a candidate retrograde messenger in long-term potentiation (LTP). The NO metabolic pathway is expressed in the cerebellar granule cell layer but its physiological role remained unknown. In this paper we have investigated the role of NO in cerebellar mossy fiber-granule cell LTP, which has postsynaptic N-methyl-d-aspartate (NMDA) receptor-dependent induction. Pre- and postsynaptic current changes were simultaneously measured by using extracellular focal recordings, and NO release was monitored with an electrochemical probe in P21 rat cerebellar slices. High-frequency mossy fiber stimulation induced LTP and caused a significant NO release (6.2 +/- 2.8 nM; n = 5) in the granular layer that was dependent on NMDA receptor as well as on nitric oxide synthase (NOS) activation. Preventing NO production by perfusing the NOS inhibitor 100 microM NG-nitro-l-arginine (L-NNA), blocking extracellular NO diffusion by 10 microM MbO2, or inhibiting the NO target guanylyl cyclase (sGC) with 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ) prevented LTP. Moreover, the NO donor 10 microM 2-(N,N-diethylamino)-diazenolate-2-oxide.Na (DEA-NO) induced LTP, which was mutually occlusive with LTP generated by high-frequency stimulation, prevented by ODQ, and insensitive to NMDA channel blockade (50 microM APV + 25 microM 7-Cl-kyn) or interruption of mossy fiber stimulation. Thus NO is critical for LTP induction at the cerebellar mossy fiber-granule cell relay. Interestingly, LTP manipulations were accompanied by consensual changes in the presynaptic current, suggesting that NO acts as a retrograde signal-enhancing presynaptic terminal excitability.     

Bidirectional synaptic plasticity at nociceptive afferents in the rat central amygdala

Glutamatergic inputs arising from the parabrachial nucleus to neurons in the lateral sector of the central amygdala were studied in vitro . Tetanic stimulation of these inputs led to LTP that did not require activation of NMDA receptors or a rise of postsynaptic calcium. LTP was accompanied by a reduction in the paired-pulse ratio, indicating that LTP results from an increase in transmitter release probability. Activation of adenylyl cyclase with forskolin potentiated these inputs with a similar reduction in paired-pulse facilitation and occluded LTP induction. LTP was inhibited by the protein kinase A blocker H89. Low-frequency stimulation led to LTD that required activation of postsynaptic NMDA receptors and a rise in postsynaptic calcium. There was no change in paired-pulse facilitation with LTD. LTD was blocked by protein phosphatase blockers calyculin and okadaic acid. We conclude that parabrachial inputs to the lateral sector of the central amygdala show presynaptic LTP that requires activation of a presynaptic protein kinase A via a calcium-dependent adenylyl cyclase while LTD at the same synapses is postsynaptic and requires a rise in postsynaptic calcium and activation of protein phosphatase.     

Conductance mechanism responsible for long-term potentiation in monosynaptic and isolated excitatory synaptic inputs to hippocampus

The biophysical mechanisms underlying long-term potentiation (LTP) were investigated in identifiable and monosynaptic excitatory inputs to hippocampal neurons. The results provide the first insights into the conductance changes that are responsible for the expression of LTP. Both current- and voltage-clamp measurements of the mossy fiber synaptic response in pyramidal neurons of region CA3 were made with a single-electrode-clamp system. The excitatory postsynaptic response was pharmacologically isolated by bathing hippocampal slices in saline containing 10 microM picrotoxin, which blocks the synaptic inhibition that normally accompanies the experimentally evoked mossy fiber response. LTP was induced by tetanically stimulating the mossy fiber input for 1 s at 100 Hz. Before and 20 min to 1 h after inducing LTP, we attempted to measure the mean excitatory postsynaptic potential (EPSP) amplitude, intrasomatic current-voltage relationship to a step (RN) or alpha function (AN) current waveform, membrane time constant (tau m), spike threshold (T50), peak excitatory postsynaptic current amplitude (IP), synaptic conductance increase (delta G), and synaptic reversal potential (VR); but adequate assessments of all eight of these were not always obtained for every cell that was studied. The induction of LTP increased the mean (+/- SE) EPSP amplitude form 10.5 +/- 1.4 mV during the control period to 16.8 +/- 2.4 mV after the induction of LTP (n = 14; P less than 0.05). This change was not accompanied by increases in the mean value of RN (63 +/- 11 M omega before and 61 +/- 11 M omega after induction; n = 8; P greater than 0.05); AN, which approximates the effective synaptic input resistance at the soma (10.0 +/- 1.50 M omega before and 10.5 +/- 1.60 M omega after; n = 10; P greater than 0.05); or tau m (22 +/- 2 ms before and 20 +/- 2 ms after; n = 8; P greater than 0.05). There was no significant change in T50, which was also assessed with an alpha function current waveform (1.48 +/- 0.11 nA before and 1.49 +/- 0.10 nA after; n = 6; P greater than 0.05). The mean value of IP increased from 1.1 +/- 0.2 nA during the control period to 1.8 +/- 0.3 nA after inducing LTP (n = 15; P less than 0.05). Similarly, delta G increased from 30 +/- 4 nS before to 47 +/- 4 nS after induction (n = 10; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

关于海马内突触小球超微结构的辨认

用电镜技术对大白鼠海马ＣＡｌ区的突触小球超微结构作了观察，发现有二种形态的突触小球。一种是小球的突触神经成分均封闭在球内，另一种是小球内的苔状纤维终末与球外神经毯内的树突于形成轴－树突触。小球的中央轴突终末即是苔状纤维终末，它不仅与树突侧棘形成轴－棘突触，而且与树突形成轴－树突触。树－树突触在小球内亦可见到。本文就突触小球的结构成分和突触小球的概念等问题进行了讨论。     

Long-term potentiation in the hippocampal CA1 region does not require insertion and activation of GluR2-lacking AMPA receptors

Activity-dependent insertion of AMPA-type glutamate receptors is thought to underlie long-term potentiation (LTP) at Schaffer collateral fiber synapses on pyramidal cells in the hippocampal CA1 region. Although it is widely accepted that the AMPA receptors at these synapses contain glutamate receptor type 2 (GluR2) subunits, recent findings suggest that LTP in hippocampal slices obtained from 2- to 3-wk-old rodents is dependent on the transient postsynaptic insertion and activation of Ca(2+)-permeable, GluR2-lacking AMPA receptors. Here we examined whether LTP in slices prepared from adult animals exhibits similar properties. In contrast to previously reported findings, pausing synaptic stimulation for as long as 30 min post LTP induction had no effect on LTP maintenance in slices from 2- to 3-mo-old mice. LTP was also not disrupted by postinduction application of a selective blocker of GluR2-lacking AMPA receptors or the broad-spectrum glutamate receptor antagonist kynurenate. Although these results suggest that the role of GluR2-lacking AMPA receptors in LTP might be regulated during postnatal development, LTP in slices obtained from 15- to 21-day-old mice also did not require postinduction synaptic stimulation or activation of GluR2-lacking AMPA receptors. Thus the insertion and activation of GluR2-lacking AMPA receptors do not appear to be fundamental processes involved in LTP at excitatory synapses in the hippocampal CA1 region.     

Minimal stimulus parameters and the effects of hyperpolarization on the induction of long-term potentiation in the cat motor cortex

Summary The aim of the research program of which the present work is a part is to understand the neural mechanisms involved in motor learning and memory. One of the mechanisms postulated to be involved in this process is the induction of long-term potentiation (LTP) in the motor cortex. LTP can be induced in motor cortical neurons by tetanic stimulation of their afferents from the somatosensory cortex. In the present study, the effects of different stimulating parameters on the induction of LTP were examined, using in-vivo, intracellular recordings from anesthetized cats. The expression of LTP was documented by measuring the amplitude and rise-time of excitatory postsynaptic potentials (EPSPs) before and after tetanic stimulation. The minimal tetanic stimulation capable of systematically inducing LTP was found to consist of a train of stimuli at 50 Hz, 5 s. Shorter trains of stimulation produced only a short-lasting, transient potentiation. In different cells, identical stimulation parameters resulted in different degrees of potentiation of synaptic responses. Following all the stimulation trains examined, EPSP amplitudes were transiently depressed before reaching potentiated levels. The duration of this depression was directly correlated with the duration and the frequency of the tetanic stimulation. In all the cells in which LTP was induced, the variability in the amplitudes of potentiated EPSP was significantly greater than that of control EPSP amplitudes. Hyperpolarization of the postsynaptic cell, during the delivery of the tetanic stimulation, inhibited the induction of LTP. These phenomena are discussed in relation to the postulated mechanisms of LTP induction in the cortex.     

Remodelling of synaptic morphology but unchanged synaptic density during late phase long-term potentiation (LTP): a serial section electron micrograph study in the dentate gyrus in the anaesthetised rat

In anaesthetised rats, long-term potentiation (LTP) was induced unilaterally in the dentate gyrus by tetanic stimulation of the perforant path. Animals were killed 6 h after LTP induction and dendritic spines and synapses in tetanised and untetanised (contralateral) hippocampal tissue from the middle molecular layer (MML) were examined in the electron microscope using stereological analysis. Three-dimensional reconstructions were also used for the first time in LTP studies in vivo, with up to 130 ultrathin serial sections analysed per MML dendritic segment. A volume sampling procedure revealed no significant changes in hippocampal volume after LTP and an unbiased counting method demonstrated no significant changes in synapse density in potentiated compared with control tissue. In the potentiated hemisphere, there were changes in the proportion of different spine types and their synaptic contacts. We found an increase in the percentage of synapses on thin dendritic spines, a decrease in synapses on both stubby spines and dendritic shafts, but no change in the proportion of synapses on mushroom spines. Analysis of three-dimensional reconstructions of thin and mushroom spines following LTP induction revealed a significant increase in their volume and area. We also found an increase in volume and area of unperforated (macular) and perforated (segmented) postsynaptic densities. Our data demonstrate that whilst there is no change in synapse density 6 h after the induction of LTP in vivo, there is a considerable restructuring of pre-existing synapses, with shaft and stubby spines transforming to thin dendritic spines, and mushroom spines changing only in shape and volume.     

Voltage-controlled plasticity at GluR2-deficient synapses onto hippocampal interneurons

High-frequency stimulation of pyramidal cell inputs to developing (P9-12) hippocampal stratum radiatum interneurons expressing GluR2-lacking, Ca(2+)-permeable AMPA receptors produces long-term depression of synaptic transmission, if N-methyl-d-aspartate (NMDA) receptors are blocked. Here we show that these same synapses display a remarkably versatile signal integration if postsynaptic NMDA receptors are activated. At synapses expressing GluR2-deficient AMPA receptors, tetanic stimulation that activates NMDA receptors triggered long-term potentiation or depression (LTP or LTD) depending on membrane potential. LTP was elicited at most synapses when the interneuron was held at -30 mV during the stimulus train but was typically prevented by postsynaptic hyperpolarization to -70 mV, by strong depolarization to 0 mV, by d-2-amino-5-phosphonovaleric acid, or by postsynaptic injection of the Ca2+ chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid. At synapses with predominantly GluR2-containing AMPA receptors, repetitive stimulation did not change synaptic strength regardless of whether NMDA receptors were activated. The interactions among GluR2 expression, NMDA receptor expression, and membrane potential thus confer on hippocampal interneurons a distinctive means for differential decoding of high-frequency inputs, resulting in enhanced or depressed transmission depending on the functional state of the interneuron.