Activation of group I metabotropic glutamate receptors induces long-term depression in the hippocampal CA1 region of adult rats in vitro

Previous studies have implicated that long-term depression (LTD) was developmentally regulated since LTD can be readily induced by low frequency stimulation (LFS) in acute hippocampal slices prepared from juvenile but not adult animals. Here, we have examined the LTD induced by LFS (1Hz, 900 pulses) paired with a certain pattern at the Schaffer collateral-CAl synapse in adult hippocampal slices. We found that, in the 90-day-old rat hippocampus, LTD could be induced reliably by LFS paired with stronger stimulus intensity than that used during baseline recording. However, this synaptic depression could be completely abolished by application of metabotropic glutamate receptor (mGluR) antagonist (S)-amethyl-4-carboxyphenylglycine (MCPG) which had no effect on that induced by the same protocol in the 16-day-old rat hippocampus. Furthermore, preincubation with group I mGluR antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (S)-2-methyl-4-carboxyphenylglycine (LY367385), also completely prevented the LFS-induced LTD. In contrast, group II mGluR antagonist (2S)-a-ethylglutamic acid (EGLU), N-methyl-d-aspartate (NMDA) receptor antagonist APV and voltage-gated calcium channel antagonist nimodipine had no effect on the LFS-induced LTD. Taken together, these observations suggest that LFS paired with strong stimulus strength can efficiently induce group I mGluR-dependent LTD in the adult hippocampal CA1 region, proving insight into the functional significance of hippocampal mGluR-mediated LTD in learning and memory.     

Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) of the excitatory synaptic inputs plasticity in the hippocampus is believed to underlie certain types of learning and memory. Especially, stressful experiences, well known to produce long-lasting strong memories of the event themselves, enable LTD by low frequency stimulation (LFS, 3 Hz) but block LTP induction by high frequency stimulation (HFS, 200 Hz). However, it is unknown whether stress-affected synaptic plasticity has an impact on the output plasticity. Thus, we have simultaneously studied the effects of stress on synaptic plasticity and neuronal output in the hippocampal CA1 region of anesthetized Wistar rats. Our results revealed that stress increased basal power spectrum of the evoked synchronized-spikes and enabled LTD induction by LFS. The induction of stress-facilitated LTD but not LFS induced persistent decreases of the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges; However, HFS induced LTP in non-stressed animals and increased the power spectrum of the synchronized-spikes, without affecting the frequency of the spontaneous unitary discharges, but HFS failed to induce LTP in stressed animals without affecting the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges. These observations that stress-facilitated LTD induces the output plasticity through the synchronized-spikes and spontaneous unitary discharges suggest that these types of stress-related plasticity may play significant roles in distribution, amplification and integration of encoded information to other brain structures under stressful conditions.     

Interactions between LTP- and LTD-inducing stimulation in the sensorimotor cortex of the awake freely moving rat

Bidirectional modifications in synaptic efficacy are central components in models of cortical learning and memory. More recently, the regulation of synaptic plasticity according to the history of synaptic activation, termed "metaplasticity," has become a focus of research on the physiology of memory. Here we explore such interactions between long-term potentiation (LTP) and long-term depression (LTD) in the chronically prepared rat. The effects of successive high- and low-frequency stimulation were examined in sensorimotor cortex in the adult, freely moving rat. High-frequency (300 Hz) stimulation (HFS) applied to the white matter was used to induce LTP, and prolonged, low-frequency (1 Hz) stimulation (LFS) was used to induce either depotentiation or LTD. Combined stimulation (HFS/LFS or LFS/HFS) during the induction phase attenuated potentiation effects only if the LFS followed the HFS. LTD induced by LFS alone was expressed as a reduction in the amplitude of both short- and long-latency field potential components, whereas depotentiation was primarily expressed as a decrease in the amplitude of the potentiated long-latency component. In other experiments, LTP (or LTD) was induced to asymptotic levels before applying LFS (or HFS). LFS caused depotentiation of the late component but had no measurable effect on the early component. HFS reversed previously induced LTD, but the potentiation decayed more rapidly than usual. LTP and LTD therefore modulate each other in the awake, behaving rat.     

Properties of long-term synaptic plasticity and metaplasticity in organotypic slice cultures of rat hippocampus

The aim of this study was to investigate whether synaptic plasticity and metaplasticity in slice cultures of the young rat hippocampus were comparable to previously reported synaptic plasticity and metaplasticity in acute adult hippocampal slices. This is relevant since differences do exist between the preparations as a result of age and the ex vivo maintenance. We prepared and maintained slice cultures from 5- to 6-day-old rats according to the porous membrane method. After 12–16 days in vitro, extracellular low-frequency stimulation (LFS) and high-frequency stimulation (HFS) protocols were applied to the Schaffer collaterals, and extracellular field potentials were recorded in area CA1. LFS and HFS induced long-term depression (LTD) and long-term potentiation (LTP), respectively. LTP could be reversed by LFS, as could LTD by HFS 60 min after induction. Plotting the amount of LTD and LTP versus stimulation protocol demonstrated frequency-dependence of the sign and extent of plasticity. Priming activation of group 1 metabotropic glutamate receptors (mGluRs) with DHPG facilitated subsequent LTP, revealing a metaplastic effect similar to that observed in acute slices. Immunohistochemistry for group 1 mGluR subtypes mGluR1α and mGluR5 showed both receptors to be present in these cultures. We conclude that synaptic plasticity and mGluR-mediated metaplasticity are largely comparable to those effects found in acute in vitro techniques.     

Surprising similarity between mechanisms mediating low (1 Hz)-and high (100 Hz)-induced long-lasting synaptic potentiation in CA1 of the intact hippocampus

It is generally assumed that long lasting synaptic potentiation (long-term potentiation, LTP) and depression (long-term depression, LTD) result from distinct patterns of afferent activity, with high and low frequency activity favouring LTP and LTD, respectively. However, a novel form of N-methyl-d-aspartate (NMDA) receptor-dependent synaptic potentiation in the hippocampal CA1 area in vivo induced by low frequency afferent stimulation has recently been demonstrated. Here, we further characterize the mechanisms mediating this low frequency stimulation (LFS)-induced LTP in area CA1 of intact, urethane-anesthetized preparations. Consistent with previous reports, alternating, low frequency (1 Hz) stimulation of CA1 afferents originating in the contralateral CA3 area and the medial septum resulted in gradually developing, long lasting (>2 h) LTP of field excitatory postsynaptic potentials (fEPSPs) recorded in CA1. Local application of the protein synthesis inhibitor anisomycin in CA1 blocked LFS-induced LTP, as did application of H89, an inhibitor of protein kinase A. Given the apparent overlap in molecular mechanisms mediating LFS-LTP and “classic” high-frequency stimulation (HFS)-induced LTP in CA1, we examined the relation between these forms of LTP by means of occlusion experiments. LFS, delivered to synapses saturated by initial HFS, resulted in a gradually developing LTD, rather than the normally seen LTP. Conversely, initial induction of LFS-LTP reduced the amount of subsequent HFS-LTP. Together, these experiments reveal a surprising similarity in the molecular mechanisms (dependence on NMDA receptors, protein kinase A, protein synthesis) mediating LTP induced by highly distinct (1 vs. 100 Hz) induction protocols. Importantly, these findings further challenge the “high-frequency-LTP, low-frequency LTD” dogma by demonstrating that this dichotomy does not account for all types of plasticity phenomena at central synapses.     

Opiate withdrawal modifies synaptic plasticity in subicular-nucleus accumbens pathway in vivo

Subiculum receives output of hippocampal CA1 neurons and projects glutamatergic synapses onto nucleus accumbens (NAc), the subicular-NAc pathway linking memory and reward system. It is unknown whether morphine withdrawal influences synaptic plasticity in the subicular-NAc pathway. Here, we recorded the field excitatory postsynaptic potential (EPSP) within the shell of NAc by stimulating ventral subiculum in anesthetized adult rats. We found that high frequency stimulation (HFS, 200 Hz) induced long-term potentiation (LTP) but low frequency stimulation (LFS, 1 Hz) failed to induce long-term depression (LTD) in control animals. However, behavioral stress enabled LFS to induce a reliable LTD (sLTD) that was dependent on the glucocorticoid receptors. Both LTP and sLTD were prevented by the N-methyl-d-aspartate receptor antagonist AP-5. After repeated morphine treatment for 12 days, acute withdrawal (12 h) impaired LTP but had no effect on sLTD; prolonged withdrawal (4 days) restored the LTP but impaired the sLTD. Remarkably, basal synaptic efficacy reflected by baseline EPSP amplitude was potentiated in acute withdrawal but was depressed in prolonged withdrawal. Thus, acute and prolonged opiate withdrawal may cause endogenous LTP and LTD in the subicular-NAc pathway that occludes the subsequent induction of synaptic plasticity, demonstrating adaptive changes of the NAc functions during opiate withdrawal.     

An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus

We have investigated long-term synaptic depression in the CA1 region of rat hippocampal slices. Prolonged low-frequency stimulation (LFS; 900 stimuli delivered at 2 Hz) of the Schaffer collateral-commissural pathway in naïve slices did not induce long-term depression (LTD) of synaptic transmission. However, if long-term potentiation (LTP) was firstly induced in the pathway then LFS generated an LTD-like effect (i.e. depotentiation of LTP). Depotentiation could be induced 2 h (the longest time studied) after the induction of LTP and was stable for the duration of the experiment (followed for up to 40 min). The induction of depotentiation was not blocked by the N-methyl-d-aspartate receptor antagonist d-2-amino-5-phosphonopentanoate, the L-type voltage-gated Ca²⁺ channel blocker nimodipine or the nitric oxide synthase inhibitor N-nitro-l-arginine. However, the magnitude of depotentiation was reversibly reduced, in a stereoselective manner, by the specific metabotropic glutamate receptor (mGluR) antagonist (+)--methyl-4-carboxyphenylglycine. These results show that prolonged low frequency stimulation can result in an mGluR-dependent depotentiation of LTP.     

Involvement of inositol-1,4,5-trisphosphate receptors in the bidirectional synaptic plasticity induced in hippocampal CA1 neurons by 1–10 Hz low-frequency stimulation

In the present study, both potentiation and depression of the synaptic response were induced in hippocampal CA1 neurons by systematically varying the frequency of low frequency afferent stimulation (LFS) between 0.5 and 25 Hz and the pulse number between 40 and 1000. The input–response relationship for CA1 synapses showed that LFS at a higher frequency or with a smaller pulse number increased the magnitude of potentiation of the synaptic response by increasing the contribution of N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs) to induction of potentiation. One possible mechanism for this bidirectional plasticity was that specific patterns of LFS differentially activate a uniform receptor population in producing depression or potentiation of synaptic responses. However, a pharmacological study indicated that, despite their opposite effects, both the synaptic depression induced by LFS at 1 Hz and the synaptic potentiation induced by LFS at 10 Hz were triggered by co-activation of NMDARs and mGluRs at CA1 synapses. We suggest that activation of protein kinase C or inositol-1,4,5-trisphosphate receptors, both coupled to group 1 mGluRs, is involved in the bidirectional synaptic plasticity induced in hippocampal CA1 neurons by 1–10 Hz LFS.     

Spatial performance in a complex maze is associated with persistent long-term potentiation enhancement in mouse hippocampal slices at early training stages

Long-term potentiation (LTP) and long-term depression (LTD) are principal reflections of synaptic plasticity that have been implicated in learning and memory. We have previously shown that spatial learning in a newly validated complex maze is accompanied by depression of hippocampal CA1 synaptic activity in hippocampal slices of trained mice ("behavioral LTD"). In the present study, we investigated whether behavioral LTD is accompanied by alterations of subsequent LTP induced by high-frequency stimulation (HFS). Moreover, we were interested in the time course of such alterations in relation to training stage. Animals underwent 1, 2, and 8 days of spatial training in the complex maze, respectively. Hippocampal slices were taken 24 h after the last training session. We found a simultaneous decrease of basal synaptic response and increase of HFS induced LTP magnitude compared with slices of untrained animals. Synaptic plasticity was not influenced by repeated running wheel exercise in an additional control group without spatial learning. The mentioned alterations occurred already after day 2 of maze exploration parallel to the most pronounced improvement of behavioral performance but did not change thereafter until day 8 despite further learning progress. They were also found when animals were trained for 2 days and kept at rest for a subsequent 6 days. In conclusion, spatial learning may be reflected by distinct and persistent measurable alterations of synaptic plasticity in hippocampal CA1 neurons at early training stages.     

Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats

Exposure to chronic constant light (CCL) influences circadian rhythms and evokes stress. Since hippocampus is sensitive to stress, which facilitates long-term depression (LTD) in the hippocampal CA1 area, we examined whether CCL exposure influenced hippocampus-dependent spatial memory and synaptic plasticity in Wistar rats. Here we report that CCL exposure (3 weeks) disrupted 24-h cycle of locomotion activity in open field test. These rats showed shorter escape latency during initial phase of spatial learning but impaired hippocampus-dependent spatial memory without affecting the visual platform learning task in Morris water maze (MWM) compared with control rats. This effect may be due to stress adaptation as reflected by reduced thigmotaxis and anxiety-like behaviors in CCL rats. Moreover, in CA1 area of the hippocampal slices, CCL rats failed to show LTD by low frequency stimulation (LFS, 900 pulses, 1 Hz), while showed decreased short-term depression compared with control rats indicating the induction of LTD was influenced by CCL exposure. Furthermore, additional acute stress enabled LFS to induce LTD in control rats but not in CCL rats. Thus, these results suggested that CCL exposure impaired spatial memory and influenced hippocampal LTD, which may be due to stress adaptation.     

Estradiol modulates long-term synaptic depression in female rat hippocampus

Fluctuating estradiol levels in the adult, female rat modify the anatomical and functional organization of the hippocampal CA1 region. When systemic levels of estradiol are low, e.g., on estrus or in ovariectomized (OVX) rats, long-term synaptic potentiation is difficult to induce in vivo. However, little is known about the role of this ovarian hormone in long-term synaptic depression. Using multiple conditioning paradigms, we assess the magnitude of long-term depression (LTD) at CA3-CA1 synapses in vitro from adult, ovariectomized rats as a function of systemic estradiol replacement. In hippocampal slices from control OVX rats with low levels of estradiol, a low-frequency (2 Hz), asynchronous conditioning stimulation protocol does not produce LTD at 1 h postconditioning. However, this same protocol induces robust LTD in slices from estradiol-treated OVX rats. When the conditioning frequency is increased to 4 Hz, slices from both groups of rats show robust LTD in vitro. At an even higher conditioning frequency (10 Hz), the 2-Hz-based observations are reversed; no consistent changes in synaptic transmission are observed in slices from estradiol-treated OVX rats, but those from control rats (OVX + oil) show robust LTD. Thus estradiol reduces the frequency threshold for LTD induction at the CA3-CA1 synapses. Further, regardless of the conditioning frequency employed, where robust LTD is seen, its induction depends on normally functioning N-methyl-D-aspartate (NMDA) receptors during conditioning. The shift in conditioning frequency needed to elicit LTD is consistent with a decrease in NMDA receptor activation with decreasing estradiol levels.     

C-type natriuretic peptide modulates bidirectional plasticity in hippocampal area CA1 in vitro

C-type natriuretic peptide (CNP) and the natriuretic peptide receptor B (NPR-B) are expressed throughout the hippocampus. We tested whether CNP affected long-term potentiation (LTP) or long-term depression (LTD) in area CA1. Field potentials (FP) were simultaneously recorded in stratum pyramidale (SP) and stratum radiatum (SR) of area CA1 in rat hippocampal slices. To induce LTD and LTP stimulation was applied to SR in area CA1 at 1 and 5 Hz and 30–100 Hz, respectively. CNP (100 nM) increased LTD magnitude while LTP induction was impeded. Thus, in the presence of CNP the threshold for LTP induction was shifted to higher stimulus frequencies, a modulation that showed layer-specific differences in area CA1. Effects of CNP were prevented by the NPR-B antagonist HS-142-1. In the presence of the GABA_A receptor blocker bicuculline (BMI, 5 μM), CNP-mediated effects were attenuated in SP and SR. Intracellular recordings under this condition revealed that CNP significantly reduced number of action potentials generated during depolarizing current steps. The input resistance of CA1 cells and amplitude of isolated excitatory postsynaptic potential (EPSPs) were significantly increased by CNP whereas these changes were not observed in the absence of BMI. 100 Hz stimulation induced stable potentiation of the EPSP amplitude in CA1 pyramidal cells while this effect was strongly attenuated by CNP. This effect was prevented by BMI. Immunohistochemistry indicated that the peptide binds to receptors expressed on pyramidal cells and GAD_65/67-immunopositive interneurons. 20 Hz stimulation, applied for 30 s, induced LTP in SR and SP. CNP attenuated LTP in SP and reversed LTP into LTD in SR. These effects were mimicked by low-dose dl-2-amino-5-phosphonopentanoic acid (dl-APV) (10 μM) suggesting partial N-methyl d-aspartate (NMDA) receptor dependency of CNP-mediated effects. Together, our data suggest that CNP is involved in the regulation of bidirectional plasticity in area CA1 potentially by modulating GABA_A-mediated inhibition and NMDA receptors.     

Inhibitory control of LTP and LTD: stability of synapse strength

Although much is known about the induction of synaptic plasticity, the persistence of memories suggests the importance of understanding factors that maintain synaptic strength and prevent unwanted synaptic changes. Here we present evidence that recurrent inhibitory connections in the CA1 region of hippocampus may contribute to this task by modulating the relative ability to induce long-term potentiation and depression (LTP and LTD). Bath application of the gamma-aminobutyric acid (GABA) type A agonist muscimol to hippocampal slices increased the range of frequencies that produce LTD, whereas in the presence of the GABA type A antagonist picrotoxin LTD was induced only at very low stimulation frequencies (0.25-0.5 Hz). Because one source of GABAergic input to CA1 pyramidal cells is via recurrent inhibition, we tested the prediction that elevated postsynaptic spike activity would increase feedback GABA inhibition and favor the induction of LTD. By using an induction stimulation of 8 Hz, which alone produced no net change in synaptic strength, we found that stimulation presented during antidromic activation of pyramidal cell spikes induced LTD. This effect was blocked by picrotoxin. The influence of recurrent inhibition on LTP and LTD displays properties that may decrease the potential for self-reinforcing, runaway changes in synapse strength. A mechanism of this sort may help maintain patterns of synaptic strengths despite the ongoing opportunities for plasticity produced by synapse activation.     

Persistent synaptic activity produces long-lasting enhancement of endocannabinoid modulation and alters long-term synaptic plasticity

Learning and memory are thought to involve activity-dependent changes in synaptic efficacy such as long-term potentiation (LTP) and long-term depression (LTD). Recent studies have indicated that endocannabinoid-dependent modulation of inhibitory transmission facilitates induction of hippocampal LTP and that endocannabinoids play a key role in certain forms of LTD. Here, we show that repetitive low-frequency synaptic stimulation (LFS) produces persistent up-regulation of endocannabinoid signaling at hippocampal CA1 GABAergic synapses. This LFS also produces LTD of inhibitory synapses and facilitates LTP at excitatory, glutamatergic synapses. These endocannabinoid-mediated plastic changes could contribute to information storage within the brain.     

Activation of inhibitory pathways suppresses the induction of long-term potentiation in neurons of the rat lateral septal nucleus

Long-term potentiation of the hippocampal-septal pathway was examined by intracellular recording techniques. High frequency stimulation (two 100-Hz 1-s trains with a 20-s interval between them) of the hippocampal CA3 area resulted in a transient depolarization in rat lateral septal nucleus neurons. High frequency stimulation was followed by a facilitation of fast and slow inhibitory postsynaptic potentials, lasting for more than 2 h, but not by a long-lasting increase in the excitatory postsynaptic potential in the normal solution. Long-term potentiation (>2 h) of the excitatory postsynaptic potential did not appear in 74% of neurons tested, even when the fast inhibitory postsynaptic potential was blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. High frequency stimulation produced long-term potentiation of the excitatory postsynaptic potential in the Mg(2+)-free solution containing bicuculline. When the fast and slow inhibitory postsynaptic potentials were blocked by GABA(A) and GABA(B) receptor antagonists (bicuculline and CGP 55845A respectively), high frequency stimulation produced a large and sustained depolarization followed by long-term potentiation of the excitatory postsynaptic potential. However, the excitatory postsynaptic potential was not enhanced by administration of these drugs after termination of high frequency stimulation. Pretreatment with 2-amino-5-phosphonopentanoate, a NMDA receptor antagonist, resulted in loss of long-term potentiation in both sets of experiments. Paired-pulse stimulation of the hippocampal CA3 region with interstimulus intervals between 200 and 800 ms depressed the second excitatory postsynaptic potential in the presence of bicuculline. CGP 35348, a GABA(B) receptor antagonist, reversed the depression of excitatory postsynaptic potentials to facilitation. These data suggest that high frequency stimulation of hippocampal CA3 neurons enhances the efficacy of GABAergic inhibitory circuits which, in turn, depress the ability of lateral septal nucleus neurons to express long-term potentiation.     

Long-term depression in rat CA1-subicular synapses depends on the G-protein coupled mACh receptors

The subiculum, which is the primary target of CA1 pyramidal neurons and sending efferent fibres to many brain regions, serves as a hippocampal interface in the neural information processes between hippocampal formation and neocortex. Long-term depression (LTD) is extensively studied in the hippocampus, but not at the CA1-subicular synaptic transmission. Using whole-cell EPSC recordings in the brain slices of young rats, we demonstrated that the pairing protocols of low frequency stimulation (LFS) at 3 Hz and postsynaptic depolarization of -50 mV elicited a reliable LTD in the subiculum. The LTD did not cause the changes of the paired-pulse ratio of EPSC. Furthermore, it did not depend on either NMDA receptors or voltage-gated calcium channels (VGCCs). Bath application of the G-protein coupled muscarinic acetylcholine receptors (mAChRs) antagonists, atropine or scopolamine, blocked the LTD, suggesting that mAChRs are involved in the LTD. It was also completely blocked by either the Ca2+ chelator BAPTA or the G-protein inhibitor GDP-beta-S in the intracellular solution. This type of LTD in the subiculum may play a particular role in the neural information processing between the hippocampus and neocortex.     

A repetitive intracortical microstimulation pattern induces long-lasting synaptic depression in brain slices of the rat primary somatosensory cortex

Repetitive intracortical microstimulation (ICMS) applied to the rat primary somatosensory cortex (SI) in vivo was reported to induce reorganization of receptive fields and cortical maps. The present study was designed to examine the effect of such an ICMS pattern applied to layer IV of brain slices containing SI on the efficacy of synaptic input to layer II/III. Effects of ICMS on the synaptic strength was quantified for the first synaptic component (s1) of cortical field potentials (FPs) recorded from layer II/III of SI. FPs were evoked by stimulation in layer IV. The pattern of ICMS was identical to that used in vivo. However, stimulation intensity had to be raised to induce an alteration of synaptic strength. In brain slices superfused with standard ACSF, repetitive ICMS induced a short-lasting (60 min) reduction of the amplitude (-37%) and the slope (-61%) of s1 evoked from the ICMS site, while the amplitude and the slope of s1 evoked from a control stimulation site in cortical layer IV underwent a slow onset increase (13% and 50%, respectively). In brain slices superfused with ACSF containing 1.25 microM bicuculline, ICMS induced an initial strong reduction of the amplitude (-50%) and the slope (-79%) of s1 evoked from the ICMS site. These effects decayed to a sustained level of depression by -30% (amplitude) and -60% (slope). In contrast to experiments using standard ACSF, s1 evoked from the control site was not affected by ICMS. The presynaptic volley was not affected in either of the two groups of experiments. A conventional high frequency stimulation (HFS) protocol induced input-specific long-term potentiation (LTP) of the amplitude and slope of s1 (25% and 76%, respectively). Low frequency stimulation (LFS) induced input-specific long-term depression (LTD) of the amplitude and slope of s1 (24% and 30%, respectively). Application of common forms of conditioning stimulation (HFS and LFS) resulted in LTP or LTD of s1, indicating normal susceptibility of the brain slices studied to the induction of common forms of synaptic plasticity. Therefore, the effects of repetitive ICMS on synaptic FP components were considered ICMS-specific forms of short-lasting (standard ACSF) or long-lasting synaptic depression (ACSF containing bicuculline), the latter resembling neocortical LTD. Results of this study suggest that synaptic depression of excitatory mechanisms are involved in the cortical reorganization induced by repetitive ICMS in vivo. An additional contribution of an ICMS-induced modification of inhibitory mechanisms to cortical reorganization is discussed.     

Aging effects on the limits and stability of long-term synaptic potentiation and depression in rat hippocampal area CA1

Altered hippocampal synaptic plasticity may underlie age-related memory impairment. In acute hippocampal slices from aged (22-24 mo) and young adult (1-12 mo) male Brown Norway rats, extracellular excitatory postsynaptic field potentials were recorded in CA1 stratum radiatum evoked by Schaffer collateral stimulation. We used enhanced Ca(2+) to Mg(2+) ratio and paired-pulse stimulation protocol to induce maximum changes in the synaptic plasticity. Six episodes of theta-burst stimulation (TBS) or nine episodes of paired low-frequency stimulation (pLFS) were used to generate asymptotic long-term potentiation (LTP) and long-term depression (LTD), respectively. In addition, long-term depotentiation (LTdeP) or de-depression (LTdeD) from maximal LTP and LTD were examined using two episodes of pLFS or TBS. Multiple episodes of TBS or pLFS produced significant LTP or LTD in aged and young adult rats; this was not different between age groups. Moreover, there was no significant difference in the amount of LTdeP or LTdeD between aged and young adult rats. Our results show no age differences in the asymptotic magnitude of LTP or LTD, rate of synaptic modifications, development rates, reversal, or decay after postconditioning. Thus impairment of the basic synaptic mechanisms responsible for expression of these forms of plasticity is not likely to account for decline in memory function within this age range.     

Propofol-mediated impairment of CA1 long-term potentiation in mouse hippocampal slices

Propofol (2,6-diisopropylphenol) is a short-acting intravenous anesthetic. Propofol is known to impair maintenance of long-term potentiation (LTP) in synaptic responses from Schaffer collateral-commissural (SC) pathway to CA1 pyramidal cells in the hippocampus, but the threshold concentration of propofol needed to elicit this action is unknown. The actions of propofol in vivo (e.g., amnesia, sedation, hypnosis and immobility) depend on its concentration, and thus it is necessary to determine the concentration required to impair CA1 LTP in order to assess the impact of impairment in vivo. In the present study, we investigated the effects of various concentrations of propofol on synaptic plasticity, primarily by measuring LTP at SC pathway to CA1 pyramidal cell synapses in mouse hippocampal slices. Continuous application of 50 microM propofol from 20 min before tetanus stimulation suppressed potentiation of the synaptic responses by tetanus stimulation. The suppression was pronounced from 10 min post-tetanus and about 55% suppression of the potentiation was observed at 60 min after tetanus. Propofol at 5 or 20 microM did not have this effect. The presence of gamma-aminobutyric acid type A (GABA(A)) receptors antagonist, picrotoxin, abrogated the suppression of LTP by 50 microM propofol. Propofol 50 microM did not affect long-term depression (LTD). These results suggest that the suppression of hippocampal CA1 LTP via GABA(A) receptors requires a much higher propofol concentration compared with that needed to induce amnesia.     

Long-term depression is not modulated by ATP receptors in the rat CA1 hippocampal region

ATP is an important extracellular messenger in the CNS. In the hippocampus, a brain structure relevant for learning and memory processes, it acts both as a modulator and as a mediator of synaptic transmission, with implications for synaptic plasticity phenomena. Recent evidence suggests that ATP modulates activity-dependent long-term potentiation (LTP) of Schaffer collateral-CA1 synapses. However, it remains unclear if ATP also modulates LTP counterpart's phenomenon, long-term depression (LTD), in the rat hippocampus. This study investigated the effect of ATP analogues on homosynaptic LTD, induced by low-frequency stimulation of the Schaffer collaterals (1 Hz; 900 pulses) in the CA1 region of young rat hippocampal slices. The metabolically stable ATP analogues beta,gamma-ImATP (20 microM), a P2 receptor agonist, and alpha,beta-MeATP (20 microM), a preferential P2X(1,3) receptor agonist, did not modify LTD (LTD values of 14.7+/-0.5% and 14.1+/-3% for aCSF controls and of 15.1+/-4% and 19.0+/-5.2% for beta,gamma-ImATP and alpha,beta-MeATP, respectively). The ATP analogue beta,gamma-ImATP (20 microM) did not modify LTD also in the presence of the adenosine A1 receptor antagonist DPCPX (50 nM) (21.5+/-4.2% for DPCPX only and of 23.8+/-8.9% for DPCPX plus beta,gamma-ImATP). Finally, the preferential P2X(1,3) receptor antagonist NF023 (10 microM) had also no effect on LTD (18.6+/-5.2% for aCSF and of 18.7+/-5.2% for NF023). The present results suggest that ATP does not modulate activity-dependent homosynaptic LTD in the rat CA1 hippocampal region by activating P2 receptors.