The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo

Long-term plasticity, in the forms of long-term depression (LTD) and long-term potentiation (LTP), of synaptic transmission are thought to underlie memory. Biogenic amino acids modulate the expression of LTD and LTP. The serotonergic 5-hydroxytryptamine4 (5-HT4) receptor has been shown to influence learning and memory. However, little is known about the role of this receptor in synaptic plasticity. Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity. In addition, the 5-HT4 antagonist RS39604 enhances the intermediate phase of LTD and converts short-term depression into persistent LTD (>24 h), suggesting a significant role for 5-HT4 receptors in the expression of LTD in CA1. Stimulation at 10 Hz causes transient synaptic depression. However, 5-HT4 antagonist application prior to 10 Hz stimulation leads to LTD, whereas agonist application leads to LTP expression. 5-HT4 receptors thus shift the frequency-response relationship for induction of plasticity. Together, these findings suggest a key role for 5-HT4 receptors in the regulation of synaptic plasticity and the determination of the particular properties of stored synaptic information.     

Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy

No study has yet investigated whether cortical plasticity in primary motor area (M1) is abnormal in patients with progressive supranuclear palsy (PSP). We studied M1 plasticity in 15 PSP patients and 15 age-matched healthy subjects. We used intermittent theta-burst stimulation (iTBS) to investigate long-term potentiation (LTP) and continuous TBS (cTBS) to investigate long-term depression (LTD)-like cortical plasticity in M1. Ten patients underwent iTBS again 1 year later. We also investigated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in M1 with paired-pulse transcranial magnetic stimulation, tested H reflex from upper limb flexor muscles before and after iTBS, and measured motor evoked potential (MEP) input-output (I/O) curves before and after iTBS. iTBS elicited a significantly larger MEP facilitation after iTBS in patients than in healthy subjects. Whereas in healthy subjects, cTBS inhibited MEP, in patients it significantly facilitated MEPs. In patients, SICI was reduced, whereas ICF was normal. H reflex size remained unchanged after iTBS. Patients had steeper MEP I/O slopes than healthy subjects at baseline and became even more steeper after iTBS only in patients. The iTBS-induced abnormal MEP facilitation in PSP persisted at 1-year follow-up. In conclusion, patients with PSP have abnormal M1 LTP/LTD-like plasticity. The enhanced LTP-like cortical synaptic plasticity parallels disease progression.     

Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex

Although drug-induced adaptations in the prefrontal cortex (PFC) may contribute to several core aspects of addictive behaviors, it is not clear yet whether drugs of abuse elicit changes in synaptic plasticity at the PFC excitatory synapses. Here we report that, following repeated cocaine administration (15 mg/kg/day intraperitoneal injection for 5 consecutive days) with a 3-day withdrawal, excitatory synapses to layer V pyramidal neurons in rat medial prefrontal cortex (mPFC) become highly sensitive to the induction of long-term potentiation (LTP) by repeated correlated presynaptic and postsynaptic activity. This promoted LTP induction is caused by cocaine-induced reduction of gamma-aminobutyric acid (GABA)(A) receptor-mediated inhibition of mPFC pyramidal neurons. In contrast, in slices from rats treated with saline or a single dose of cocaine, the same LTP induction protocol did not induce significant LTP unless the blockade of GABA(A) receptors. Blockade of the D1-like receptors specifically prevented the cocaine-induced enhancement of LTP. Repeated cocaine exposure reduced the GABA(A) receptor-mediated synaptic currents in mPFC pyramidal neurons. Biotinylation experiments revealed a significant reduction of surface GABA(A) receptor alpha1 subunit expression in mPFC slices from repeated cocaine-treated rats. These findings support an important role for cocaine-induced enhancement of synaptic plasticity in the PFC in the development of drug-associated behavioral plasticity.     

Olfactory learning modifies predisposition for long-term potentiation and long-term depression induction in the rat piriform (olfactory) cortex

Learning-related modifications in predisposition for long-term potentiation (LTP) and long-term depression (LTD) were studied in brain slices of the rat piriform cortex following olfactory learning. Rats were trained to discriminate between pairs of odors until they demonstrated rule learning. We have previously shown that such training is accompanied by enhanced neuronal excitability and increased synaptic transmission in the intrinsic synaptic pathway. Here we show that the susceptibility for further enhancing synaptic connectivity by inducing LTP in slices from trained rats is markedly reduced after training, compared with slices from pseudo-trained and naive rats. Accordingly, while 900 stimuli at 1 Hz did not induce LTD in slices from control rats, it induced significant LTD in slices from trained rats. Post-tetanic potentiation (PTP) was also reduced after training, indicating that synaptic release is enhanced after odor learning, as previously suggested. We suggest that learning-related cellular modifications and activity-dependent synaptic plasticity share a common mechanism in the primary olfactory cortex. Our data also support the prediction generated according to the sliding modification threshold theory that learning should be accompanied by reduced capability of inducing LTP and increased susceptibility for LTD induction.     

Learning-facilitated synaptic plasticity at CA3 mossy fiber and commissural-associational synapses reveals different roles in information processing

Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)-CA3 and commissural-associational (AC)-CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region.     

长时程增强及长时程抑制与全麻药关系的研究进展

长时程增强(long-term potentation,LTP)和长时程抑制(long-term depression,LTD)作为突触可塑性的两种不同表达方式,是学习记忆活动的细胞水平的生物学基础,与记忆的形成和维持有关.近年来许多研究表明,全身麻醉药的遗忘、镇静催眠及镇痛等效应与影响神经系统的突触可塑性即LTP和LTD有密切的关系.现就近年来LTP及LTD与全身麻醉药之间的最新进展作一综述.     

The hippocampal CA1 region and dentate gyrus differentiate between environmental and spatial feature encoding through long-term depression

Novel spatial information is encoded in the hippocampus by plastic changes of synaptic properties. Novel space consists of several types of information that may evoke differential synaptic responses in individual hippocampal subregions. To examine this possibility, we recorded field potentials from the dentate gyrus (DG) and CA1 region in freely moving adult rats. Stimulation protocols that were marginally subthreshold for the induction of persistent long-term potentiation (LTP) or long-term depression (LTD) were implemented, concurrent with exposure to novel spatial information. We found that in both hippocampal subregions, exploration of a novel empty hole board facilitated LTP. However, LTD facilitation was subregion specific and dependent on the nature of the cues. In the CA1 region, partially concealed cues had a facilitatory effect on LTD. LTD in the DG was facilitated by large directional cues. Thus, although LTP was facilitated uniformly in both areas by the same novel environment, LTD was facilitated in a region-specific manner, based on the nature of the cue. This implies that spatial changes within an environment elicit local changes of synaptic weights dependent on the type of information and, hence, generate a complete cognitive map as a consequence of cooperation of synaptic plasticity in all participating subregions.     

Temporary occlusion of associative motor cortical plasticity by prior dynamic motor training

A novel Hebbian stimulation paradigm was employed to examine physiological correlates of motor memory formation in humans. Repetitive pairing of median nerve stimulation with transcranial magnetic stimulation over the contralateral motor cortex (paired associative stimulation, PAS) may decrease human motor cortical excitability at interstimulus intervals of 10 ms (PAS10) or increase excitability at 25 ms (PAS25). The properties of this plasticity have previously been shown to resemble associative timing-dependent long-term depression (LTD) and long-term potentiation (LTP) as established in vitro. Immediately after training a novel dynamic motor task, the capacity of the motor cortex to undergo plasticity in response to PAS25 was abolished. PAS10-induced plasticity remained unchanged. When retested after 6 h, PAS25-induced plasticity recovered to baseline levels. After training, normal PAS25-induced plasticity was observed in the contralateral training-naive motor cortex. Motor training did not reduce the efficacy of PAS25 to enhance cortical excitability when PAS10 was interspersed between the training and application of the PAS25 protocol. This indicated that the mechanism supporting PAS25-induced plasticity had remained intact immediately after training. Behavioral evidence was obtained for continued optimization of force generation at a time when PAS25-induced plasticity was blocked in the training motor cortex. Application of the PAS protocols after motor training did not prevent the consolidation of motor skills evident as performance gains at later retesting. The results are consistent with a concept of temporary suppression of associative cortical plasticity by neuronal mechanisms involved in motor training. Although it remains an open question exactly which element of motor training was responsible for this effect, our findings may link dynamic properties of LTP formation, as established in animal experiments, with human motor memory formation and possibly dynamic motor learning.     

Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex

Monocular deprivation leads to clear physiological and anatomical changes in the visual cortex known as ocular dominance plasticity. Protein kinase A (PKA) is necessary for ocular dominance plasticity, while protein kinase G (PKG) is not. We have now tested the role of PKA and PKG in long-term potentiation (LTP) and long-term depression (LTD). We have shown that PKA inhibitors have a major effect on both LTP and LTD in the visual cortical slices, whereas a PKG inhibitor affects LTP but not LTD. The PKA activator, 8-chloroadenosine-3',5'-monophosphorothioate, Sp-isomer (Sp-8-Cl-cAMPS), by itself induces a slowly rising form of LTP, which is occluded by theta-burst stimulation (TBS)-induced LTP. These results support the point that the PKA signaling pathway is crucial for neuronal plasticity in visual cortex, and the dissociation of the role of PKA and PKG in long-term synaptic plasticity in the visual cortex suggests that LTP alone is not sufficient to support ocular dominance plasticity, or LTD plays a more fundamental role than LTP in ocular dominance plasticity.     

Human θ burst stimulation enhances subsequent motor learning and increases performance variability

Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.     

Volatile anesthetics and synaptic transmission in the central nervous system

Long-lasting changes in the synaptic efficacy of signaling between neurons in the central nervous system are thought to be involved in memory consolidation and recall. Such long-lasting changes were first demonstrated by Bliss et al. in 1973. They found that high frequency stimulation to the hippocampus produced an increase in the amplitude of excitatory postsynaptic potentials, which lasted at least for hours. This phenomenon is known as long-term potentiation (LTP). LTP occurs in many synaptic pathways, and some forms of LTP appear to be triggered by the influx of calcium through NMDA receptors. General anesthetics are thought to affect LTP, since clinically relevant concentrations of volatile anesthetics seem to modify ligand-gated ion channels such as glutamate receptors and GABA(A) receptors. Previous studies have shown that volatile anesthetics such as isoflurane and sevoflurane enhance GABA(A) receptor-mediated inhibition, suggesting that general anesthesia is produced, at least in part, by enhancing neural inhibition mediated by GABA(A) receptors. This review focuses on recent research concerning the effects of volatile anesthetics on synaptic transmission, synaptic plasticity, and clinically important diseases imparing synaptic transmission in the central nervous system.     

Beta-adrenoreceptors comprise a critical element in learning-facilitated long-term plasticity

A novel spatial environment consists of several different types of information that may be encoded by cellular information storage mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). Arousal, mediated, for example, by activation of the noradrenergic system, is a critical factor in information acquisition and may enhance the encoding of novel spatial information. Using electrophysiological recordings of hippocampal responses in freely moving rats during spatial learning, we investigated the role of the beta-adrenoreceptor in Schaeffer collateral-CA1 synaptic plasticity. We found that novel exploration of spatial context facilitates induction of LTD that is inhibited by intracerebroventricular application of the beta-adrenoreceptor antagonist, propranolol. Long-lasting homosynaptic LTD, that was electrically induced by low-frequency stimulation, was unaffected by the antagonist. Although application of a beta-adrenoreceptor agonist (isoproterenol) did not affect electrically induced LTD, agonist application facilitated short-term depression (STD) into LTD and mimicked the augmentation, through spatial exploration, of STD into LTD. Exploration of a novel empty environment facilitated LTP that was prevented by application of propranolol. These results suggest that beta-adrenoreceptors may facilitate encoding of spatial information through synaptic plasticity in the hippocampus and that noradrenaline is a key factor in effective information acquisition.     

Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning

Several lines of evidence suggest that schizophrenia (SCZ) is associated with disrupted plasticity in the cortex. However, there is little direct neurophysiological evidence of aberrant long-term potentiation (LTP)-like plasticity in SCZ and little human evidence to establish a link between LTP to learning and memory. LTP was evaluated using a neurophysiological paradigm referred to as paired associative stimulation (PAS). PAS involves pairing of median nerve electric stimulation with transcranial magnetic stimulation (TMS) over the contralateral motor cortex (for abductor pollicis brevis muscle activation) delivered at 25-ms interstimulus interval. This pairing was delivered at a frequency of 0.1 Hz for 30 min. LTP was reflected by the change in motor evoked potentials (MEPs) before and after PAS. In addition, motor skill learning was assessed using the rotary pursuit task. Compared with healthy subjects, patients with SCZ demonstrated significant MEP facilitation deficits following PAS and impaired rotary-pursuit motor learning. Across all subjects there was a significant association between LTP and motor skill learning. These data provide evidence for disrupted LTP in SCZ, whereas the association between LTP with motor skill learning suggests that the deficits in learning and memory in SCZ may be mediated through disordered LTP.     

D4 dopamine receptors modulate NR2B NMDA receptors and LTP in stratum oriens of hippocampal CA1

Dopamine plays an important role in synaptic plasticity and learning and is involved in the pathogenesis of various neurological and psychiatric disorders. Here, we reveal staining of dopaminergic fibers in stratum oriens of the mouse hippocampal CA1 region, a finding that is consistent with earlier reports. Furthermore, we examined the effect of dopamine agonists on NMDAR-dependent early long-term potentiation (LTP) (40 min) during γ-aminobutyric acid (GABA)(A)-mediated blockade. LTP of the AMPA component was strongly reduced in stratum oriens but barely affected in stratum radiatum. This layer-specific effect was caused by D4 receptor activation, which augmented the inactivation of synaptic NMDAR-mediated currents (NMDA EPSCs) during LTP induction through a Ca(2+)-dependent G-protein-independent mechanism. A similar dopaminergic modulation of both NMDA EPSCs and LTP was also observed in mice constitutively lacking NR2A but was absent in mice lacking NR2B in principal forebrain neurons. Together, these experiments strongly indicate that dopaminergic modulation of early LTP in stratum oriens occurs through NMDARs containing NR2B subunits via D4Rs. Thus, a dopamine hyperfunction in stratum oriens may result in NMDAR hypofunction that could affect both normal and pathological conditions.     

The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.     

Mechanisms of LTP Induction in Rat Motor Cortex in vitro

The motor cortex displays remarkable plasticity in responseto changes in sensory and motor experience; however, the synapticmechanisms underlying functional plasticity are not known. Itis believed that synaptic processes that alter the strengthof neuronal connections, such as long-term potentiation (LTP),are mechanisms by which synaptic circuits are modified by experience,resulting in functional adaptations. In the present study, weexamined the mechanisms of LTP of synaptic responses in layersII/III to vertical (stimulation in layers V/VI) and horizontal(stimulation in layers II/III) inputs, in slices from rat motorcortex. Tetanic stimulation in layers V/VI or II/III inducedLTP in 60% of the field potentials (n = 20) and in 73% of theintracellularty recorded postsynaptic potentials (n = 33). LTPwas induced in cells with firing patterns characteristic ofregular-spiking, fast-spiking, or bursting cells. LTP was expressed,for the most part in kainate/AMPA receptor-mediated responses;however, potentiation of NMDA receptor-mediated components wasalso observed. Induction of LTP was prevented when either NMDAreceptors or dihydro-pyridine-sensitive Ca²⁺ channels (DSCCs)were blocked, although blockade of DSCCs was less effectivein preventing LTP induction. Based on the present data and previousLTP studies, we suggest that in many forms of LTP more thanone mechanism participates in the induction process. The presentfindings may be relevant to the synaptic mechanisms underlyingfunctional plasticity in motor cortex.     

Isoflurane Blocks Synaptic Plasticity in the Mouse Hippocampus

Background: The volatile anesthetic isoflurane depresses glutamatergic transmission. In this study, the authors investigated the effects of isoflurane on the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices from the juvenile and adult mouse hippocampus. Both forms of synaptic plasticity involve the activation of glutamate receptors.

Methods: Field excitatory postsynaptic potentials and excitatory postsynaptic currents from neurons in the CA1 area were evoked by stimulation of the Schaffer collateral-commissural pathway. Two independent synaptic inputs were stimulated. Clinically relevant concentrations (0.2-0.3 mm) of isoflurane were added to the perfusion solution.

Results: Field excitatory postsynaptic potentials from slices of juvenile and adult mice were depressed to 37.3 +/- 6.1% and 58.3 +/- 7.4%, respectively, and excitatory postsynaptic currents were reduced to 36.7 +/- 5.4% by isoflurane. A brief tetanic stimulation (100 Hz, 1 s) induced stable LTP of field excitatory postsynaptic potentials. In the presence of isoflurane, tetanization failed to induce LTP. The effect of isoflurane on LTP induction was reversible and could be prevented by antagonizing [gamma]-aminobutyric acid type A receptors (GABAA). Low-frequency stimulation (1 Hz/900 pulses) induced LTD. In the presence of isoflurane, low-frequency stimulation failed to induce LTD.     

Evidence for the specificity of intracortical inhibitory dysfunction in asymptomatic concussed athletes

Sports concussions affect thousands of individuals every year and are a major public health concern. Still, little is known about the long-term and cumulative effects of concussions on brain neurophysiology. The principal objective of this study was to investigate the long-lasting effects of multiple sports concussions on sensorimotor integration and somatosensory processing in a sample of 12 concussed athletes and 14 non-concussed athletes of similar age (mean, 23 years) and education (mean, 16 years). Right median nerve stimulation was paired with transcranial magnetic stimulation (TMS) of the left primary motor cortex to investigate sensorimotor integration with short latency afferent inhibition (SAI) and long latency afferent inhibition (LAI) at five interstimulus intervals (18, 20, 22, 100, 200 msec). Somatosensory evoked potentials (SEP) were recorded from the left centro-parietal region. We also investigated primary motor cortex inhibitory mechanisms with three TMS protocols: cortical silent period, long interval intracortical inhibition, and short interval intracortical inhibition. Motor evoked potentials were recorded from the right abductor pollicis brevis muscle. No differences were observed between groups for SAI, LAI, and SEP. However, cortical silent period duration was prolonged and long interval intracortical inhibition was enhanced in the concussed group. These findings suggest that multiple sports concussions lead to specific, long-term neurophysiological dysfunctions of intracortical inhibitory mechanisms in primary motor cortex while somatosensory processing and sensorimotor integration are spared. This study provides additional evidence for the presence of specific and stable alterations of GABA(B) receptor activity in primary motor cortex that may be of clinical value for prognosis and diagnosis.     

Isoflurane blocks synaptic plasticity in the mouse hippocampus

BACKGROUND: The volatile anesthetic isoflurane depresses glutamatergic transmission. In this study, the authors investigated the effects of isoflurane on the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices from the juvenile and adult mouse hippocampus. Both forms of synaptic plasticity involve the activation of glutamate receptors. METHODS: Field excitatory postsynaptic potentials and excitatory postsynaptic currents from neurons in the CA1 area were evoked by stimulation of the Schaffer collateral-commissural pathway. Two independent synaptic inputs were stimulated. Clinically relevant concentrations (0.2-0.3 mM) of isoflurane were added to the perfusion solution. RESULTS: Field excitatory postsynaptic potentials from slices of juvenile and adult mice were depressed to 37.3 +/- 6.1% and 58.3 +/- 7.4%, respectively, and excitatory postsynaptic currents were reduced to 36.7 +/- 5.4% by isoflurane. A brief tetanic stimulation (100 Hz, 1 s) induced stable LTP of field excitatory postsynaptic potentials. In the presence of isoflurane, tetanization failed to induce LTP. The effect of isoflurane on LTP induction was reversible and could be prevented by antagonizing gamma-aminobutyric acid type A receptors (GABAA). Low-frequency stimulation (1 Hz/900 pulses) induced LTD. In the presence of isoflurane, low-frequency stimulation failed to induce LTD. CONCLUSIONS: The prevention of the isoflurane-induced depression of LTP by the GABAA antagonist picrotoxin suggests an involvement of GABAA receptors. An enhancement of the efficacy of GABA-mediated inhibitory synaptic transmission prevents the depolarization of the postsynaptic membrane during tetanus, necessary for the induction of use-dependent alteration of synaptic strength. An impairment of these processes may be a cause for the transient loss of recall and cognitive impairment after anesthesia in juvenile and adult brains.     

Long-term depression in freely moving rats is dependent upon strain variation, induction protocol and behavioral state

Hippocampal long-term depression (LTD) comprises a persistent decrease in synaptic transmission which is induced by repeated low-frequency stimulation (LFS). Although LTD has been widely demonstrated in the CA1 region in vitro, very few positive reports of LTD in vivo have occurred. In this study, the conditions under which homosynaptic LTD occurs in the CA1 region of freely moving rats was investigated. Three rat strains were studied: Wistar, Sprague-Dawley and Hooded Lister. Whereas Wistar and Sprague-Dawley rats expressed optimal LTD following 1 Hz LFS, Hooded Lister rats showed no LTD when tested in an LFS range of 1-10 Hz. Exposure to marked stress transiently enhanced LTD obtained in Wistar and Sprague-Dawley rats, but did not facilitate LTD induction in the LTD-resistant strain. It was possible to induce long-term potentiation with high-frequency stimulation, although the profile of LTP was different in each strain. These data suggest that the expression of LTD varies according to the strain of rat used and is tightly dependent upon stimulation frequency. In addition the behavioral state of the animal may influence LTD expression. These data may explain, in part, the conflicting reports with regard to the inducibility of hippocampal LTD in vivo.