Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.     

Metaplasticity of the human trigeminal blink reflex

Although synaptic plasticity in the human cerebral cortex is governed by metaplasticity, whether a similar mechanism operates at brainstem level is unknown. In this study in healthy humans we examined the effects and interactions induced by pairing supraorbital nerve high-frequency electrical stimulation (HFS) protocols on the R2 component of the trigeminal blink reflex [Mao, J.B. & Evinger, C (2001) J Neurosci., 21:RC151(1-4)]. Changes in the R2 component were tested by pairing three different priming stimulation protocols inducing long-term potentiation (LTP)-like or long-term depression (LTD)-like effects (LTP-HFS and LTD-HFS), or no change (CONTROL-HFS) with a subsequent test LTP-HFS. Additionally, to examine changes in the R2 component induced by nonspecific factors, two CONTROL-HFS sessions were paired. Priming LTP-, LTD- or CONTROL-HFS potentiated, inhibited or left unchanged the area of the R2 component. Regardless of the type of priming LTP-, LTD- or CONTROL-HFS, the test LTP-HFS induced negligible differences in the R2 component. When two CONTROL-HFS sessions were paired, the test CONTROL-HFS increased the latency and markedly reduced the duration and area of the R2 component. The analysis of the normalized data across the first three experimental sessions, corrected for the inhibitory effects found in the fourth experiment, showed that the test LTP-HFS potentiated the R2 component area of the trigeminal blink reflex only when preceded by a priming LTD-HFS. We propose that homosynaptic metaplasticity might operate in the brainstem circuitry of the blink reflex.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.     

Differential roles of basolateral and central amygdala on the effects of uncontrollable stress on hippocampal synaptic plasticity

The amygdala is considered central in mediating stress-related changes of hippocampal functions. However, it remains unclear whether different amygdala subnuclei have different roles in coordinating stress effects. Here, we report that stress exposure caused an immediate increase of extracellular signal-regulated kinase (ERK)1/2 phosphorylation in the hippocampal area CA1 and the basolateral amygdala (BLA) and after a delay in the central amygdala (CEA). Exposure to the novel environment following stress increased ERK1/2 phosphorylation in the CEA, but reversed the stress-induced increase of ERK1/2 phosphorylation in the hippocampal area CA1 and the BLA. Either ERK1/2 inhibitor U0126 or N-methyl-D-aspartate (NMDA) receptor antagonist DL-(-)-2-amino-5-phosphonopentanoic acid (APV) administration into the BLA, but not the CEA, blocked the stress effects on hippocampal long-term potentiation (LTP) and long-term depression. Novelty-exploration-induced reversal of stress effects was prevented when animals were injected U0126 or APV into the CEA, but not the BLA, before subjected to the novel environment. The ability of novelty exploration to reverse the stress effects was mimicked by intra-CEA infusion of NMDA. These findings suggest that BLA ERK1/2 signaling pathway is critical to mediate the stress effects on hippocampal synaptic plasticity; the activation of CEA ERK1/2, in contrast, appears to mediate the reversal of stress effects.     

Alterations in the balance of protein kinase and phosphatase activities and age-related impairments of synaptic transmission and long-term potentiation

Aging is associated with an impaired ability to maintain long-term potentiation (LTP), but the underlying cause of the impairment remains unclear. To gain a better understanding of the cellular and molecular mechanisms responsible for this impairment, the synaptic transmission and plasticity were studied in the CA1 region of hippocampal slices from adult (6-8 months) and poor-memory (PM)-aged (23-24 months) rats. The one-way inhibitory avoidance learning task was used as the behavioral paradigm to screen PM-aged rats. With intracellular recordings, CA1 neurons of PM-aged rats exhibited a more hyperpolarized resting membrane potential, reduced input resistance, and increased amplitude of afterhyperpolarization and spike threshold, compared with those in adult rats. Although a reduction in the size of excitatory synaptic response was observed in PM-aged rats, no obvious differences were found between adult and PM-aged rats in the pharmacological properties of excitatory synaptic response, paired-pulse facilitation, or frequency-dependent facilitation, which was tested with trains of 10 pulses at 1, 5, and 10 Hz. Slices from the PM-aged rats displayed significantly reduced early-phase long-term potentiation (E-LTP) and late-phase LTP (L-LTP), and the entire frequency-response curve of LTP and LTD is modified to favor LTD induction. The susceptibility of time-dependent reversal of LTP by low-frequency afferent stimulation was also facilitated in PM-aged rats. Bath application of the protein phosphatase inhibitor, calyculin A, enhanced synaptic response in slices from PM-aged, but not adult, rats. In contrast, application of the cAMP-dependent protein kinase inhibitors, Rp-8-CPT-cAMPS and KT5720, induced a decrease in synaptic transmission only in slices from the adult rats. Furthermore, the selective beta-adrenergic receptor agonist, isoproterenol, and pertussis toxin-sensitive G-protein inhibitor, N-ethylmaleimide, effectively restored the deficit in E-LTP and L-LTP of PM-aged rats. These results demonstrate that age-related impairments of synaptic transmission and LTP may result from alterations in the balance of protein kinase/phosphatase activities.     

Exploring strategies to alleviate caregiver burden: Effects of the National Long‐Term Care insurance scheme in Japan

The ever‐increasing population of older people with disabilities, including dementia, has been accompanied by a corresponding growth in the number of family caregivers, who are themselves at risk of developing mental and physical health problems. As a result, the need for practical and effective approaches for alleviating caregiver burden has become a major public health concern. One approach involves the development of public policy initiatives to allow the caregiver burden to be borne partly by society as a whole, rather than falling solely on individuals. In 2000, Japan introduced a National Long‐Term Care (LTC) insurance scheme that requires adults over the age of 40 years to pay compulsory monthly premiums, with one aim of the program being to reduce caregiver burden. The present paper reviews the effects of this scheme on caregivers' and the general public's perception of caregiver burden and assesses what other measures are needed to further reduce and/or prevent burden. Drawing on recent studies, four questions are addressed: (i) have caregivers' attitudes towards caregiving changed since the implementation of the scheme; (ii) do services provided under the scheme alleviate caregiver burden; (iii) what are the general public's attitudes to and understanding of family caregiving; and (iv) what is the general public's level of understanding of dementia? Results from recent studies suggest that the LTC insurance scheme in Japan appears to be an effective measure for alleviating the burden of caregiving among current family caregivers, but larger studies are needed to determine overall effectiveness.     

Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats

Thyroid hormone deficiency during a critical period of development profoundly affects cognitive functions such as attention, learning, and memory, but the synaptic alterations underlying these deficits remain unexplored. The present study examines the effect of congenital hypothyroidism on long-term synaptic plasticity. This plasticity is believed to be essential for learning and memory and for activity-dependent regulation of synapse formation in the developing brain. We found that the neonatal expression of long-term potentiation (LTP), long-term depression (LTD), depotentiation, and de-depression in hippocampal slices from hypothyroid animals was similar to that of controls. To examine the postnatal development of these plasticities, we used slices from neonatal (2-3 weeks) and adult (7-8 weeks) rats. This work demonstrates that the ability to express all these forms of synaptic plasticity is reduced in an age-dependent manner in control rats. LTP and depotentiation are also downregulated in adult hypothyroid rats, but we have found that de-depression is not affected during maturation. In addition, these animals express LTD at ages at which controls fail to induce it. In contrast, input/output experiments have shown greater levels of basal synaptic efficacy in hypothyroid adults, and this effect is probably related to the higher probability of release observed by paired-pulse experiments. Nevertheless, these effects appear to be unrelated to the differences observed in long-term synaptic plasticity, as no correlation was found between basal synaptic efficacy and the degree of LTD and de-depression. Furthermore, the NMDA-receptor antagonist amino-phosphonopentanoic acid (APV) completely blocked LTD, which suggests a postsynaptic locus of this alteration. Because LTD has been associated with novelty acquisition, we suggest that the greater LTD observed in adult hypothyroid rats might be related to the hyperactivity of these animals. However, other possibilities such as a retarded maturation of synaptic plasticity must be taken into account.     

Long‐lasting modulation of synaptic plasticity in rat hippocampus after early‐life complex febrile seizures

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia‐induced febrile seizures indicate that prolonged febrile seizures early in life have long‐lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity‐dependent synaptic plasticity (long‐term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural‐evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long‐term potentiation and reduced long‐term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long‐term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long‐term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.     

Chronic in vivo optogenetic stimulation modulates neuronal excitability,spine morphology,and Hebbian plasticity in the mouse hippocampus

Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.     

Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3‐CA1 synapses

Glycogen synthase kinase‐3 (GSK3), particularly the isoform GSK3β, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3α has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3β rather than GSK3α has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long‐term synaptic plasticity in knockin mice with a point mutation in GSK3α or GSK3β that prevents their inhibitory regulation. We report that only the mutation in GSK3α affects long‐term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3α should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo

Repeated vivid recalls or flashbacks of traumatic memories and memory deficits are the cardinal features of post-traumatic stress disorder (PTSD). The underlying mechanisms are not fully understood yet. Here, we examined the effects of very strong fear conditioning (20 pairings of a light with a 1.5-mA, 0.5-s foot shock) and subsequent reexposure to the conditioning context (chamber A), a similar context (chamber B), and/or to the fear conditioned stimulus (CS) (a light) on synaptic plasticity in the hippocampal CA1 area in anesthetized Sprague-Dawley rats. The conditioning procedure resulted in very strong conditioned fear, as reflected by high levels of persistent freezing, to both the contexts and to the CS, 24 h after fear conditioning. The induction of long-term potentiation (LTP) was blocked immediately after fear conditioning. It was still markedly impaired 24 h after fear conditioning; reexposure to the conditioning chamber A (CA) or to a similar chamber B (CB) did not affect the impairment. However, presentation of the CS in the CA exacerbated the impairment of LTP, whereas the CS presentation in a CB ameliorated the impairment so that LTP induction did not differ from that of control groups. The induction of long-term depression (LTD) was facilitated immediately, but not 24 h, after fear conditioning. Only reexposure to the CS in the CA, but not reexposure to either chamber A or B alone, or the CS in chamber B, 24 h after conditioning, reinstated the facilitation of LTD induction. These data demonstrate that unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm can have profound effects on hippocampal synaptic plasticity, which may aid to understand the mechanisms underlying impairments of hippocampus-dependent memory by stress or in PTSD.     

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.     

Spatial analysis of spike-timing-dependent LTP and LTD in the CA1 area of hippocampal slices using optical imaging

Spike-timing-dependent long-term potentiation (LTP) and long-term depression (LTD) were investigated in the CA1 area of hippocampal slices using optical imaging. A pair of electrical pulses were used to stimulate the Schaffer-commissural collateral and the stratum oriens with various sets of relative timing (tau) between the two stimuli. These sets of paired pulses gave rise to LTP/LTD, whose induction was closely related to tau, and their profiles were classified into two types depending on their layer specific location along the dendrite. One was characterized by a symmetric time window observed in the proximal region of the stratum radiatum (SR) and the other by an asymmetric time window in the distal region of the SR. Bath application of bicuculline (gamma-aminobutyric acid [GABA] receptor antagonist) to hippocampal slices revealed that GABAergic interneuron projections were responsible for the symmetry of a time window.     

Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking

The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal‐directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico‐striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate. We use our novel, computationally efficient simulator, NeuroRD, to simulate stochastic interactions both within and between dendritic spines. Dopamine release during theta burst and 20‐Hz stimulation was extrapolated from fast‐scan cyclic voltammetry data collected in mouse striatal slices. Our results show that the combined activity of several key plasticity molecules correctly predicts the occurrence of either LTP, LTD, or no plasticity for numerous experimental protocols. To investigate spatial interactions, we stimulate two spines, either adjacent or separated on a 20‐μm dendritic segment. Our results show that molecules underlying LTP exhibit spatial specificity, whereas 2‐arachidonoylglycerol exhibits a spatially diffuse elevation. We also implement changes in NMDA receptors, adenylyl cyclase, and G protein signaling that have been measured following chronic alcohol treatment. Simulations under these conditions suggest that the molecular changes can predict changes in synaptic plasticity, thereby accounting for some aspects of alcohol use disorder.     

Evaluation of human fetal neural stem/progenitor cells as a source for cell replacement therapy for neurological disorders: properties and tumorigenicity after long-term in vitro maintenance

It is expected that human neural stem/progenitor cells (hNS/PCs) will some day be used in cell replacement therapies. However, their availability is limited because of ethical issues, so they have to be expanded to obtain sufficient amounts for clinical application. Moreover, in-vitro-maintained hNS/PCs may have a potential for tumorigenicity that could be manifested after transplantation in vivo. In the present study, we demonstrate the in vitro and in vivo properties of long-term-expanded hNS/PCs, including a 6-month bioluminescence imaging (BLI) study of their in vivo tumorigenicity. hNS/PCs cultured for approximately 250 days in vitro (hNS/PCs-250) exhibited a higher growth rate and greater neurogenic potential than those cultured for approximately 500 days in vitro (hNS/PCs-500), which showed greater gliogenic potential. In vivo, both hNS/PCs-250 and -500 differentiated into neurons and astrocytes 4 weeks after being transplanted into the striatum of immunodeficient mice, and hNS/PCs-250 exhibited better survival than hNS/PCs-500 at this time point. We also found that the grafted hNS/PCs-250 survived stably and differentiated properly into neurons and astrocytes even 6 months after the surgery. Moreover, during the 6-month observation period by BLI, we did not detect any evidence of rapid tumorigenic growth of the grafted hNS/PCs, and neither PCNA/Ki67-positive proliferating cells nor significant malignant invasive features were detected histologically. These findings support the idea that hNS/PCs may represent a nontumorigenic, safe, and appropriate cell source for regenerative therapies for neurological disorders.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.