ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices

Mitogen-activated protein kinase (MAPK) cascade is essential for synaptic plasticity and learning. In the hippocampus, three different MAPK subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun NH2-terminal protein kinase (JNK), selectively regulate activity-dependent glutamate receptor trafficking during long-term potentiation (LTP), long-term depression (LTD), and depotentiation after LTP, respectively. Although LTP and LTD at cerebellar parallel fibre (PF)-Purkinje cell synapses are thought to be controlled by glutamate receptor trafficking, the involvement of MAPK subfamilies has not been systemically studied in cerebellar slice preparations. To clarify the role of the MAPK cascade in cerebellar LTD, we performed biochemical and electrophysiological analyses using ICR mouse cerebellar slices. Immunoblot analyses using phosphorylation-specific antibodies for MAPKs revealed that among the three MAPKs, ERK1/2 was specifically activated by phorbol ester, which could induce LTD in cerebellar slices. In addition, U0126, a specific inhibitor of the MAPK kinase-ERK1/2 pathway, abrogated the induction of LTD in cerebellar slices, whereas SB203580 and SP600125, specific inhibitors of p38 MAPK and JNK, respectively, had no effect. Although metabotropic glutamate receptor 1 (mGluR1) has been suggested as a possible downstream target of ERK1/2 in cell-culture preparations, mGluR1-activated slow excitatory postsynaptic currents (EPSCs) were not affected by U0126 treatment in slices. These findings indicate that unlike hippocampal LTD mediated by p38 MAPK, glutamate receptor trafficking during cerebellar LTD was regulated by a distinct mechanism involving ERK1/2 in slice preparations.     

Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses

It is commonly accepted that the hippocampus is critically involved in the explicit memory formation of mammals. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum can be classified according to their firing properties into burst-spiking and regular-spiking cells. In the present study we demonstrate that burst-spiking and regular-spiking cells show fundamentally different forms of low frequency-induced synaptic plasticity in rats. In burst-spiking cells, low-frequency stimulation (at 0.5–5 Hz) induces frequency-dependent long-term depression (LTD) with a maximum at 1 Hz. This LTD is dependent on the activation of NMDAR and masks an mGluR-dependent long-term potentiation (LTP). In contrast, in regular-spiking cells low-frequency stimulation induces an mGluR-dependent LTP that masks an NMDAR-dependent LTD. Both processes depend on postsynaptic Ca²⁺-signaling as BAPTA prevents the induction of synaptic plasticity in both cell types. Thus, mGluR-dependent LTP and NMDAR-dependent LTD occur simultaneously at CA1-subiculum synapses and the predominant direction of synaptic plasticity relies on the cell type investigated. Our data indicate a novel mechanism for the sliding-threshold model of synaptic plasticity, in which induction of LTP and LTD seems to be driven by the relative activation state of NMDAR and mGluR. Our observation that the direction of synaptic plasticity correlates with the discharge properties of the postsynaptic cell reveals a novel and intriguing mechanism of target specificity that may serve in tuning the significance of neuronal information by trafficking hippocampal output onto either subicular burst-spiking or regular-spiking cells.     

β3 integrin is dispensable for conditioned fear and Hebbian forms of plasticity in the hippocampus

Integrins play key roles in the developing and mature nervous system, from promoting neuronal process outgrowth to facilitating synaptic plasticity. Recently, in hippocampal pyramidal neurons, β3 integrin (ITGβ3) was shown to stabilise synaptic AMPA receptors (AMPARs) and to be required for homeostatic scaling of AMPARs elicited by chronic activity suppression. To probe the physiological function for ITGβ3-dependent processes in the brain, we examined whether the loss of ITGβ3 affected fear-related behaviours in mice. ITGβ3-knockout (KO) mice showed normal conditioned fear responses that were similar to those of control wild-type mice. However, anxiety-like behaviour appeared substantially compromised and could be reversed to control levels by lentivirus-mediated re-expression of ITGβ3 bilaterally in the ventral hippocampus. In hippocampal slices, the loss of ITGβ3 activity did not compromise Hebbian forms of plasticity - neither acute pharmacological disruption of ITGβ3 ligand interactions nor genetic deletion of ITGβ3 altered long-term potentiation (LTP) or long-term depression (LTD). Moreover, we did not detect any changes in short-term synaptic plasticity upon loss of ITGβ3 activity. In contrast, acutely disrupting ITGβ1-ligand interactions or genetic deletion of ITGβ1 selectively interfered with LTP stabilisation whereas LTD remained unaltered. These findings indicate a lack of requirement for ITGβ3 in the two robust forms of hippocampal long-term synaptic plasticity, LTP and LTD, and suggest differential roles for ITGβ1 and ITGβ3 in supporting hippocampal circuit functions.     

Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice

Nitric oxide (NO) is a retrograde messenger involved in the processes of learning and memory. The role of the endothelial isoform of nitric oxide synthase (eNOS) in striatal synaptic plasticity was investigated in eNOS-deficient (eNOS(-/-)) and wild type (WT) mice. Tetanic stimulation of cortical afferents in WT mice evoked either long-term potentiation (LTP), or long-term depression (LTD) of cortico-striatal transmission. Both these plasticity related phenomena were NMDA-receptor-dependent; LTD was blocked by sulpiride, a dopamine D2-receptor antagonist. LTP occurrence in slices from eNOS(-/-) mice was significantly reduced when compared with WT mice. The NOS inhibitor NL-ARG reduced the occurrence of LTP and increased the occurrence of LTD in WT mice, resembling the balance of LTP/LTD in eNOS(-/-) mice. Impairment of NO-synthesis thus shifts striatal plasticity towards LTD. This indicates a possible involvement of eNOS from endothelia in neuronal modulation.     

Anisomycin activates p38 MAP kinase to induce LTD in mouse primary visual cortex

Anisomycin is both a well-established protein synthesis inhibitor and a potent activator of the p38/JNK MAPK pathway. It has been used to block the late phase of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In this study, we have found that anisomycin produces a time-dependent decline in the magnitude of the field EPSP (fEPSP) in acute brain slices of mouse primary visual cortex. This anisomycin-mediated fEPSP depression occludes NMDA receptor-dependent LTD induced by low-frequency stimulation (LFS). In contrast, two other protein synthesis inhibitors, emetine and cycloheximide, have no effect either on baseline synaptic transmission or on LTD. Moreover, the decline of the fEPSP caused by anisomycin can be rescued by the application of the p38 inhibitor SB203580 but not by the JNK inhibitor SP600125. These results indicate that activation of p38 MAPK by anisomycin induces LTD and subsequently occludes electrically induced LTD. Also, the occlusion of LFS-LTD by anisomycin suggests that common mechanisms may be shared between the two forms of synaptic depression. Consistent with this view, bath application of a membrane permeant peptide derived from the carboxyl tail of GluR2 subunit of AMPA receptor, which specifically blocks regulated AMPA receptor endocytosis, thereby preventing the expression of LFS-induced LTD, significantly reduced the anisomycin-induced decline of the fEPSP. In conclusion, our results indicate that anisomycin produces long-lasting depression of AMPA receptor-mediated synaptic transmission by activating p38 MAPK-mediated endocytosis of APMA receptors in mouse primary visual cortex.     

Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment

Behavioural experience (e.g. chronic stress, environmental enrichment) can have long-lasting effects on cognitive functions. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as hippocampus, we tested whether behaviour has also long-lasting effects on synaptic plasticity by examining the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices of hippocampal CA1 obtained from rats either 7-9 months after social defeat (behavioural stress) or 3-5 weeks after 5-week exposure to environmental enrichment. Compared with age-matched controls, defeated rats showed markedly reduced LTP. LTP was even completely impaired but LTD was enhanced in defeated and, subsequently, individually housed (during the 7-9-month period after defeat) rats. However, increasing stimulus intensity during 100-Hz stimulation resulted in significant LTP. This suggests that the threshold for LTP induction is still raised and that for LTD lowered several months after a short stressful experience. Both LTD and LTP were enhanced in environmentally enriched rats, 3-5 weeks after enrichment, as compared with age-matched controls. Because enrichment reduced paired-pulse facilitation, an increase in presynaptic release, facilitating both LTD and LTP induction, might contribute to enhanced synaptic changes. Consistently, enrichment reduced the number of 100-Hz stimuli required for inducing LTP. But enrichment may also actually enhance the range of synaptic modification. Repeated LTP and LTD induction produced larger synaptic changes in enriched than in control rats. These data reveal that exposure to very different behavioural experiences can produce long-lasting effects on the susceptibility to synaptic plasticity, involving pre- and postsynaptic processes.     

Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD). Protein kinases and protein phosphatases are important players in the induction of both LTP and LTD, and the serine/threonine protein phosphatase-1 (PP1), in particular, has emerged as a key phosphatase in these processes. The goal of the present study was to assess the contribution of PP1 to bidirectional plasticity and examine the impact of a partial inhibition of PP1 on LTP, LTD and depotentiation in the mouse hippocampus. For this, we used transgenic mice expressing an active PP1 inhibitor (I-1*) inducibly in forebrain neurons. We show that partial inhibition of PP1 by I-1* expression alters the properties of bidirectional plasticity by inducing a shift of synaptic responses towards potentiation. At low-frequency stimulation, PP1 inhibition decreases LTD in a frequency-dependent fashion. It favours potentiation over depression at intermediate frequencies and increases LTP at high frequency. Consistently, it also impairs depotentiation. These results indicate that the requirement of bidirectional plasticity for PP1 is frequency-dependent and that a broad range of plasticity is negatively constrained by PP1, a feature that may correlate with the property of PP1 to constrain learning efficacy and promote forgetting.     

Induction mechanisms and modulation of bidirectional burst stimulation-induced synaptic plasticity in the hippocampus

Spike bursting is an important physiological mode of the hippocampus. Whereas the rules of spike timing-dependent synaptic plasticity are well defined for pairs of single action potentials (APs) and excitatory postsynaptic potentials (EPSPs), long-term modification of synaptic responses is much less understood for more complex pre- and postsynaptic spike patterns. We induced a burst stimulation (BS)-associated form of synaptic plasticity in rat CA1 hippocampal slices by repeatedly pairing three EPSPs with a burst of APs induced by postsynaptic current injection. In distinct groups of cells, this induction paradigm resulted in long-term potentiation (LTP), long-term depression (LTD) or no change in synaptic strength. LTP was N -methyl- d -aspartate receptor-dependent, whereas LTD could be blocked by a metabotropic glutamate receptor antagonist or inhibition of Ca²⁺ influx through voltage-activated Ca²⁺ channels. LTP was predicted by a more depolarized membrane potential and a higher initial AP frequency. LTD was facilitated by a larger time interval between the last EPSP and its preceding AP. We conclude from these findings that associative BS induces a bidirectional form of long-term synaptic plasticity that cannot be fully explained by spike timing rules. Postsynaptic membrane potential and Ca²⁺ influx further influence the sign and magnitude of synaptic modification. LTP and LTD have distinct mechanisms and can be selectively modulated. This supports the concept of two independent coincidence detectors for LTP and LTD, and extends the physiological options to modulate synaptic plasticity and maintain a putative balance between potentiation and depression in synaptic networks.     

Chemical LTD in the CA1 field of the hippocampus from young and mature rats

Within the hippocampal formation, two forms of long-lasting synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), can be induced which require the activation of NMDA receptors. Interestingly, it has been shown that both LTP and LTD are reduced in adult animals. Recently, a new chemical protocol has been described which elicits LTD in the CA1 field of the hippocampus. Application of 20 microM NMDA for 3 min results in a stable and long-lasting decrease in the evoked synaptic responses. We used this protocol to induce LTD in hippocampal slices from young and adult rats and show that this form of LTD is AP5-sensitive and can be blocked by the protein phosphatase inhibitor cyclosporin A in slices from adult animals. In contrast to electrical LTD (induced by prolonged low frequency stimulation), the extent of chemical LTD was not different between the young and adult rats. These findings indicate that the intracellular signal transduction cascades involved in long-lasting synaptic depression are still intact in adult animals.     

Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons

In the adult rat hippocampus, activation of N-methyl-d-aspartate receptors (NMDARs) is required for the induction of certain forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Several studies have indicated the opposing role of synaptic NMDARS (S-NMDARs) versus extrasynaptic NMDARs (ES-NMDARs) in CREB-dependent gene regulation and neuronal survival/death. The contribution of ES-NMDARs in synaptic plasticity, however, remains unclear. Here we investigated the contribution of ES-NMDARs on LTD induction in CA1 neurons of rat hippocampal slices. ES-NMDARs were selectively activated by theta burst stimulation (TBS) after selective blockade of S-NMDARs with pairing of 5 Hz stimulation and MK-801, an irreversible use-dependent antagonist of NMDARs. Application of TBS in naïve slices evoked a transient potentiation. In contrast, the activation of ES-NMDARs evoked a robust LTD. These results suggest the involvement of ES-NMDARs in LTD induction.     

Impairment of catecholamine systems during induction of long-term potentiation at hippocampal CA1 synapses in HPC-1/syntaxin 1A knock-out mice

The membrane protein HPC-1/syntaxin 1A is believed to play a key role in synaptic vesicle exocytosis, and it was recently suggested to be required for synaptic plasticity. Despite evidence for the function of HPC-1/syntaxin 1A in synaptic plasticity, the underlying cellular mechanism is unclear. We found that although fast synaptic transmission and long-term depression were unaffected, HPC-1/syntaxin 1A knock-out (STX1A(-/-)) mice showed impaired long-term potentiation (LTP) in response to theta-burst stimulation in CA1 hippocampal slices. The impairment in LTP was rescued by the application of forskolin, an adenylyl cyclase activator, or more robust stimulation, suggesting that cAMP/protein kinase A signaling was suppressed in these mice. In addition, catecholamine release from the hippocampus was significantly reduced in STX1A(-/-) mice. Because HPC-1/syntaxin 1A regulates exocytosis of dense-core synaptic vesicles, which contain neuromodulatory transmitters such as noradrenaline, dopamine and 5-HT, we examined the effect of neuromodulatory transmitters on LTP induction. Noradrenaline and dopamine enhanced LTP induction in STX1A(-/-) mice, whereas catecholamine depletion reduced LTP induction in wild-type mice. Theses results suggest that HPC-1/syntaxin 1A regulates catecholaminergic systems via exocytosis of dense-core synaptic vesicles, and that deletion of HPC-1/syntaxin 1A causes impairment of LTP induction.     

Prenatal morphine exposure enhances seizure susceptibility but suppresses long-term potentiation in the limbic system of adult male rats

The present study examined the effects of prenatal morphine exposure on NMDA-dependent seizure susceptibility in the entorhinal cortex (EC), and on activity-dependent synaptic plasticity at Schaffer collateral and perforant path synapses in the hippocampus. During perfusion with Mg(2+)-free ACSF, an enhancement of epileptiform discharges was found in the EC of slices from prenatally morphine-exposed male rats. A submaximal tetanic stimulation (2x50 Hz/1 s) in control slices elicited LTP at the Schaffer collateral-CA1 synapses, but neither LTP nor LTD was evoked at the perforant path-DG synapses. In slices from prenatally morphine-exposed adult male rats, long-term potentiation of synaptic transmission was not observed at Schaffer collateral-CA1 synapses, while the submaximal tetanus now elicited frank LTD of synaptic EPSPs at perforant path synapses. These data suggest that prenatal morphine exposure enhances the susceptibility of entorhinal cortex to the induction of epileptiform activity, but shifts long-term plasticity of hippocampal synapses in favor of LTD.     

Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring

Clinical studies demonstrate that prenatal stress causes cognitive deficits and increases vulnerability to affective disorders in children and adolescents. The underlying mechanisms are not yet fully understood. Here, we reported that prenatal stress (10 unpredictable, 1 s, 0.8 mA foot shocks per day during gestational days 13-19) impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in hippocampal CA1 region in slices of the prenatal stressed offspring (5 weeks old). Cross-fostering neonate offspring by the prenatal stressed or control mothers did not change the effects of prenatal stress on the hippocampal LTP and LTD. Furthermore, prenatal stress enhanced the effects of acute stress on the hippocampal LTP and LTD and impaired spatial learning and memory in the Morris water maze in the young rat offspring. Therefore, prenatal stress alters synaptic plasticity and enhances the effects of acute stress on synaptic plasticity in the hippocampus, which may be the mechanism for the impaired spatial learning and memory in young rat offspring.     

Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro

The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit differences in their regulation of synaptic plasticity, suggesting that these receptors may subserve separate functional roles in information storage. In addition, although effects in vivo are consistently described, conflicting reports of the involvement of mGluRs in hippocampal synaptic plasticity in vitro exist. We therefore addressed the involvement of mGluR1 and mGluR5 in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region of adult male rats in vitro . The mGluR1 antagonist (S)-(+)-α-amino-4-carboxy-2-methylbenzene-acetic acid (LY367385) impaired both induction and late phases of both LTP and LTD, when applied before high-frequency tetanization (HFT; 100 Hz) or low-frequency stimulation (LFS; 1 Hz), respectively. Application after either HFT or LFS had no effect. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), when given before HFT, inhibited both the induction and late phases of LTP. When given after HFT, late LTP was inhibited. MPEP, given prior to LFS, impaired LTD induction, although stable LTD was still expressed. Application after LFS significantly impaired late phases of LTD. Activation of protein synthesis may comprise a key mechanism underlying the group I mGluR contribution to synaptic plasticity. The mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) converted short-term depression into LTD. Effects were prevented by application of the protein synthesis inhibitor anisomycin, suggesting that protein synthesis is triggered by group I mGluR activation to enable persistency of synaptic plasticity. Taken together, these data support the notion that both mGluR1 and mGluR5 are critically involved in bidirectional synaptic plasticity in the CA1 region and may enable functional differences in information encoding through LTP and LTD.     

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

Using mice with a targeted disruption of the adenosine A1 receptor (A1R), we examined the role of A1Rs in hippocampal long-term potentiation (LTP), long-term depression (LTD), and memory formation. Recordings from the Shaffer collateral-CA1 pathway of hippocampal slices from adult mice showed no differences between theta burst and tetanic stimulation-induced LTP in adenosine A1 receptor knockout (A1R-/-), heterozygote (A1R+/-), and wildtype (A1R+/+) mice. However, paired pulse facilitation was impaired significantly in A1R-/- slices as compared to A1R+/+ slices. LTD in the CA1 region was unaffected by the genetic manipulation. The three genotypes showed similar memory acquisition patterns when assessed for spatial reference and working memory in the Morris water maze tasks at 9 months of age. However, 10 months later A1R-/- mice showed some deficits in the 6-arm radial tunnel maze test. The latter appeared, however, not due to memory deficits but to decreased habituation to the test environment. Taken together, we observe normal spatial learning and memory and hippocampal CA1 synaptic plasticity in adult adenosine A1R knockout mice, but find modifications in arousal-related processes, including habituation, in this knockout model.     

Long-lasting synaptic loss after repeated induction of LTD: independence to the means of LTD induction

Short- and long-lasting synaptic plasticity is assumed to be the cellular basis of short- and long-lasting memory, respectively. However, the cellular consequences leading to the long-lasting synaptic plasticity, assumed to include the processes of synapse formation and elimination, remain unknown. Using hippocampal slices maintained stably in culture, we found previously that the repeated induction of long-term potentiation (LTP) triggered a slowly developing long-lasting enhancement in synaptic transmission strength accompanied by synapse formation, which was separate from LTP itself. We recently reported a phenomenon apparently of a mirror-image effect. The repeated activations of metabotropic glutamate receptor (mGluR), which induces long-term depression (LTD), triggered a long-lasting reduction in synaptic strength accompanied by synapse elimination. To clarify whether the reported long-lasting effect was specific to the drugs used previously and whether the effect was specific to mGluR-mediated LTD, we exposed the cultured slices repeatedly to another Group I metabotropic glutamate receptor (mGluR) agonist, an N-methyl-d-aspartate receptor agonist, and a Na+/K+-pump inhibitor. All these treatments resulted in an equivalent long-lasting synaptic reduction/elimination when repeated three times, indicating that the repeated LTD induction leads to synapse elimination. The independence of synapse elimination to the means of LTD induction suggests that the signals leading to short-term plasticity and long-term plasticity are independent. Detailed inspections in the representative case of mGluR activation revealed that the reduction in synaptic strength developed with a approximately 1-week delay from the decrease in the number of synaptic structures. This synapse elimination should be unique as it is activity-dependent rather than inactivity-dependent.     

Impaired hippocampal long-term potentiation in microtubule-associated protein 1B-deficient mice

Microtubule-associated protein (MAP)1B-heterozygous (MAP1B+/-) mice are deficient in the expression of MAP1B in the hippocampus, cerebellum, and olfactory cortex. Although MAP1B+/- mice showed half the normal levels of MAP1B protein, they had no measurable amounts of phosphorylated MAP1B. High-frequency theta burst stimulation of Schaffer collateral-CA1 axons in hippocampal slices from MAP1B+/- mice elicited long-term potentiation (LTP) that decayed rapidly to baseline, in contrast to the non-decremental LTP exhibited by age-matched wild-type slices. A separate group of MAP1B+/- and wild-type slices was examined for a longer time course of 3 hr post-tetanus in response to multiple high-frequency stimulus trains that induced saturated LTP. MAP1B+/- slices showed marked reductions in both immediate post-tetanic potentiation and LTP that decayed much more rapidly than that in wild-type slices. The induction of LTP was associated with a rapid dephosphorylation of MAP1B within 5-15 min post-tetanus, suggesting that the normal expression of MAP1B and conversion to a dephosphorylated state may be a cellular mediator of cytoskeletal alterations necessary for long-term activity-dependent synaptic plasticity.     

Loss of interneuron LTD and attenuated pyramidal cell LTP in Trpv1 and Trpv3 KO mice

TRPV (transient receptor potential, vanilloid) channels are a family of nonselective cation channels that are activated by a wide variety of chemical and physical stimuli. TRPV1 channels are highly expressed in sensory neurons in the peripheral nervous system. However, a number of studies have also reported TRPV channels in the brain, though their functions are less well understood. In the hippocampus, the TRPV1 channel is a novel mediator of long‐term depression (LTD) at excitatory synapses on interneurons. Here we tested the role of other TRPV channels in hippocampal synaptic plasticity, using hippocampal slices from Trpv1, Trpv3 and Trpv4 knockout (KO) mice. LTD at excitatory synapses on s. radiatum hippocampal interneurons was attenuated in slices from Trpv3 KO mice (as well as in Trpv1 KO mice as previously reported), but not in slices from Trpv4 KO mice. A previous study found that in hippocampal area CA1, slices from Trpv1 KO mice have reduced tetanus‐induced long‐term potentiation (LTP) following high‐frequency stimulation; here we confirmed this and found a similar reduction in Trpv3 KO mice. We hypothesized that the loss of LTD at the excitatory synapses on local inhibitory interneurons caused the attenuated LTP in the mutants. Consistent with this idea, blocking GABAergic inhibition rescued LTP in slices from Trpv1 KO and Trpv3 KO mice. Our findings suggest a novel role for TRPV3 channels in synaptic plasticity and provide a possible mechanism by which TRPV1 and TRPV3 channels modulate hippocampal output. © 2013 Wiley Periodicals, Inc.