Adenosine modulates synaptic plasticity in hippocampal slices from aged rats

Adenosine is known to modulate synaptic plasticity in the hippocampus of young animals through activation of adenosine A1 receptors. The objective of the present study is to investigate whether the modulatory role of adenosine on phenomena of synaptic plasticity is maintained or modified in the hippocampus of aged animals. We compared the effects of the selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 50 nM), on paired-pulse facilitation (PPF), long-term depression (LTD), long-term potentiation (LTP) and depotentiation elicited in hippocampal slices taken from young adult (5-6 weeks) and old (2 years old) male Wistar rats. DPCPX attenuated PPF both in young (1.64 +/- 0.05 vs. 1.76 +/- 0.05%, n = 6) and in old rats (1.33 +/- 0.05 vs. 1.55 +/- 0.1%, n = 6). LTD was only observed in the presence of DPCPX in both young (21.3 +/- 0.6%, n = 4) and old rats (14.4 +/- 0.9%, n = 6). LTP induced by high-frequency stimulation (HFS) was not significantly different in young and old animals, in the presence or in the absence of DPCPX. A larger depotentiation was observed in the presence of DPCPX in young rats (27.6 +/- 4.4% vs. 16.8 +/- 4.7%, n = 7) as well as in old rats (41.3 +/- 5.1% vs. 16.1 +/- 2.7%, n = 6). LTP induced by theta-burst stimulation was observed only in the presence of DPCPX (53.9 +/- 4.9%, n = 5) in young rats, but could be obtained either in the control solution (81.8 +/- 17.9%, n = 7) or in the presence of DPCPX (98.5 +/- 24.2%, n = 7) in old rats. The modulatory role of endogenous adenosine on synaptic plasticity is generally maintained in aged animals. Drugs interfering with adenosine A1 receptor effects could then be used in old animals to modify synaptic plasticity with relevant behavioural consequences.     

The effects of chronic lead exposure on long-term depression in area CA1 and dentate gyrus of rat hippocampus in vitro

Long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity, are believed to underlie the mechanisms of learning and memory. Previous studies have demonstrated that low-level lead exposure can impair the induction and maintenance of LTP in vivo and in vitro. The present study was carried out to investigate whether the low-level lead exposure affected the induction and maintenance of LTD. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices in adult rats (50–65 days) to study the alterations of LTD in area CA1 and dentate gyrus (DG) of hippocampus following chronic lead exposure. The input–output (I/O) curves before conditioning in both areas showed no evident alterations in basic synaptic transmission between the control and lead exposure groups. In area CA1, the mean amplitude of EPSP slope in control rats (61±11%, n=15) decreased significantly greater than that in lead-exposed rats (78±8%, n=8, P<0.05) following low frequency stimulation (LFS, 1 Hz, 15 min), which lasted at least 45 min. In area DG, with application of the same LFS, the LTD was induced in control rats (72±22%, n=8), while the LFS failed to induce LTD in lead-exposed rats (100±26%, n=8). These results showed that chronic lead exposure affected the induction of LTD in both area CA1 and DG. The effect of lead on synaptic plasticity in area CA1 was also investigated. The alteration of the amplitude of LTP in hippocampal slices caused by lead was reexamined in order to compare with that on LTD (control: 189±23, n=5; lead-exposed: 122±12, n=10). The result demonstrated that low-level lead exposure could reduce the range of synaptic plasticity, which might underlie the dysfunction of learning and memory caused by chronic lead exposure.     

Effect of ganglioside on synaptic plasticity of hippocampus in lead-exposed rats in vivo

Synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD) and depotentiation (DP), is important for learning and memory. Previous studies proved that chronic lead exposure especially during early post-natal development induced impairment on synapse plasticity. The purpose of this study is to evaluate the effect of ganglioside on the lead-induced impairments of LTP and DP in rat dentate gyrus in vivo. The experiments were carried out in three groups of rats (control, lead-exposed, ganglioside-treated lead-exposed, respectively). The input-output (I/O) function, pair pulses reaction, excitatory post-synaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (70-90 days) in response to stimulation applied to the lateral perforant path. The results show that (1) chronic lead exposure impaired LTP/DP measured on both EPSP slope and PS amplitude in DG area of the hippocampus. (2) The amplitudes of LTP/DP of lead-exposed group were significantly increased by supplying ganglioside. These results suggest intraperitoneally injection with ganglioside could reverse the lead-induced impairments of synaptic plasticity in rats and might be effective in attenuating the cognitive deficits induced by lead.     

Synaptic plasticity in the hippocampus is modulated by behavioral state

The possible influence of the sleep-waking cycle on evoked neurotransmission and on the induction of long-term potentiation (LTP) and depression (LTD) was studied in the perforant path-granule cell system. Freely moving rats received a high-frequency stimulus train (8 bursts at 400 Hz) during slow-wave sleep (SWS), rapid eye movement (REM) sleep, and a still-alert (SAL) behavioral state. Trains applied during SAL and REM reliably elicited LTP of the excitatory postsynaptic potential (EPSP) slope, population spike height, and spike onset latency. Granule cell excitability was also enhanced, as indicated by a leftward shift of the EPSP-population spike (E-S) relation. In contrast, tetanization in SWS rarely produced 'classical' LTP and often failed to elicit any lasting change in field potentials. Furthermore, the following types of E-S change occurred almost exclusively after tetanization in SWS: (1) LTP of the EPSP accompanied by depression of the population spike, and (2) E-S potentiation without a change in EPSP. When LTP occurred, however, its magnitude was independent of the animal's behavioral state at the time of the train. In agreement with previous reports, the efficacy of low-frequency neurotransmission varied with behavioral state. A modulation index (MI) was introduced to quantify the difference between field potentials evoked in SAL and SWS. Interestingly, both the occurrence and magnitude of LTP were related to the strength of the MI, as determined in each rat before the train. After trains, the state-dependent modulation of transmission was maintained and was superimposed on LTP and LTD. The results suggest that synaptic plasticity is dynamically modulated during the sleep-wakefulness cycle.     

Developmental Shift From Long-term Depression to Long-term Potentiation at the Mossy Fibre Synapses in the Rat Hippocampus

During development, in the CA1 hippocampal region, long-term potentiation (LTP) starts appearing at postnatal (P) day 7 and reaches its maximal expression towards the end of the second postnatal week. However, LTP is often preceded by long-term depression (LTD), an activity-dependent and long-lasting reduction of synaptic strength. LTD can be induced by sustained, low-frequency stimulation of the afferent pathway and is dependent on activation of N -methyl-D-aspartate (NMDA) receptors. We report here that, in the CA3 hippocampal region, during a critical period of postnatal development, between P6 and P14, a high-frequency stimulation train (100 Hz, 1 s) to the mossy fibres in the presence of the NMDA receptor antagonist (+)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP; 20 μM) induced LTD. The depression of the amplitude of the field excitatory postsynaptic potential (EPSP) was 28 ± 7% ( n = 21). This form of LTD was NMDA-independent and synapse-specific. When a tetanus was applied in the presence of CPP and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX; 50 μM), which blocked the field EPSP, it failed to induce LTD upon washout of CNQX. LTD was probably postsynaptic in origin since it did not affect paired-pulse facilitation. A rise in extracellular calcium concentration (from 2 to 4 mM) produced LTP instead of LTD. At the end of the second postnatal week, the same high-frequency stimulation train to the mossy fibres induced LTP as in adult neurons. Functional changes in synaptic connections during development may control membrane depolarization and the amount of intracellular calcium necessary to trigger either LTD or LTP.     

Activation of the medial septal area attenuates LTP of the lateral perforant path and enhances heterosynaptic LTD of the medial perforant path in aged rats

Age-related memory impairments may be due to dysfunction of the septohippocampal system. The medial septal area (MSA) provides the major cholinergic projection to the hippocampus and is critical for memory. Knowledge of the neurobiological mechanisms by which the cholinergic system can attenuate age-related memory loss can facilitate the development of effective cognitive enhancers. At present, one of the best neurobiological models of memory formation is long-term potentiation/long-term depression (LTP/LTD). In previous studies, intraseptal infusion of the muscarinic agonist oxotremorine, which excites MSA neurons, improved memory in aged rats. The present study examined LTP and LTD in aged Fisher 344 rats following intraseptal infusion of oxotremorine. LTP and LTD were assessed using the slope of the EPSP recorded from the hilar region of the dentate gyrus. Induction of LTP was blocked in the lateral perforant path, but not in the medial perforant path, following intraseptal infusions of oxotremorine. The generation and amplitude of heterosynaptic LTD was enhanced in the medial perforant path, but not in the lateral perforant path. The results provide evidence that pharmacological activation of the MSA can modulate LTP and LTD in the hippocampus of aged rats. The implications of these results with respect to memory and synaptic plasticity in the hippocampus are discussed.     

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

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

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

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

Opposite effects of lead exposure on taurine- and HFS-induced LTP in rat hippocampus

The effect of lead exposure on taurine-induced long-term potentiation (LTP(TAU)) was examined and compared with high-frequency stimulation-induced one (LTP(HFS)). Field excitatory postsynaptic potentials (fEPSP) and fiber volley (FV) in area CA1 of hippocampal slice were recorded in control and lead-exposed rats. In contrast to the inhibitory effects of lead exposure on LTP(HFS), the amplitude of LTP(TAU) in the lead-exposed rats (199.3+/-13.7%, n=12) was significantly larger than that in controls (152.3+/-17.0%, n=12). It was also observed that taurine induced greater FV potentiation in lead-exposed rats (162.6+/-9.0%, n=10) than controls (132.1+/-6.9%, n=11). In addition, after a previous HFS, sequent perfusion of taurine could further increase the synaptic efficacy in lead-exposed rats. These results provide the first evidence that chronic lead exposure has opposite effects on the two types of LTP resulting from different lead toxicity sites.     

Permissive role of interneurons in corticostriatal synaptic plasticity

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.     

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.     

Effects of stimulus frequency and age on bidirectional synaptic plasticity in the dentate gyrus of freely moving rats

We investigated the frequency-dependent transition from homosynaptic long-term depression (LTD) to long-term potentiation (LTP) at the lateral perforant pathway/dentate gyrus synapse in adult (90 days of age) and immature (15 days of age) awake, freely moving rats. Dentate-evoked field potentials were recorded and analyzed using the population spike amplitude and the field EPSP slope measures following sustained stimulation (900 pulses) of the lateral perforant pathway at various frequencies (1, 3, 7, 30, 50, or 200 Hz). Our results indicate that both the strength and the direction (LTP or LTD) of synaptic plasticity vary as a function of activation frequency: sustained low-frequency stimulation ranging from 1 to 7 Hz results in depression of activated synapses, whereas high-frequency stimulation (30-200 Hz) produces potentiation. In addition, a significant (P < 0.01) ontogenetic shift in the frequency of transition from LTD to LTP was observed; the transition frequency in immature animals was significantly lower than that obtained in adult animals. These observations agree strongly with the prediction of the Bienenstock-Cooper-Munro theory of synapse modification, indicating perhaps a neurophysiological basis for this theoretical model of learning in the dentate gyrus of awake behaving rats.     

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

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

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

Only ‘de novo’ long-term depression (LTD) in the rat hippocampus in vitro is blocked by the same low concentration of FK506 that blocks LTD in the visual cortex

It has been proposed that the long-term depression (LTD) seen following low frequency stimulation (LFS) in the rat hippocampus involves calcineurin. We have tested this by examining the effect of FK506, a macrolide which blocks calcineurin at nanomolar concentrations, on synaptic transmission in the rat hippocampal slice at a concentration of 1 μM which has been shown to block LTD in the visual cortex. The effect of FK506 on long-term potentiation (LTP) and spontaneous transmitter release was also studied. The magnitude of LTD induced by LFS was 16.7 ± 2.4% in control which was not significantly different from the 22.3 ± 3.0% seen in the same preparations after exposure to FK506 for 25–30 min. In contrast the magnitude of LTD induced ‘de novo’ in preparations exposed to FK506 was significantly reduced. FK506 had no significant effect on LTP, miniature EPSP frequency, miniature EPSP amplitude, resting membrane potential or input resistance. These results, therefore, support the hypothesis that calcineurin is involved in ‘de novo’ LTD but it appears that an event is triggered by LFS whereby FK506-insensitive LTD can subsequently be activated by a second episode of LFS.     

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-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.     

Effects of the novel NMDA receptor antagonist, CGP 39551, on field potentials and the induction and expression of LTP in the dentate gyrus in vivo.

The effects of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CGP 39551 [the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid], on extracellular field potentials and long-term potentiation (LTP) induced in the dentate gyrus by stimulation of the perforant path were studied in anesthetized rats. CGP 39551 attenuated the population spike (PS) and excitatory postsynaptic potential (EPSP) amplitude of dentate field potentials, reduced the NMDA receptor-mediated component of train-evoked burst potentials, and prevented the induction of LTP. The decrease in PS and EPSP amplitude produced by CGP 39551 was observed mainly in non-potentiated synaptic populations; potentiated field potentials were only minimally affected by drug treatment. These results are consistent with receptors may contribute in a tonic manner to the state of dentate granule cell excitability. Finally, the differential modulation of potentiated and non-potentiated synapses by CGP 39551 suggests that a change in some properties of postsynaptic AMPA receptors is involved in the expression of LTP.     

Long-term depression and long-term potentiation in horizontal connections of the barrel cortex

Synaptic plasticity of horizontally orientated connections between barrels, in the barrel cortex of adult mice, was studied in slice preparations cut across rows of barrels. Field potentials were evoked in the middle of one barrel column (in layer IV or V) and recorded in the neighbouring barrel (in layer IV and V). In layer IV, long-term depression (LTD) by 26.5 +/- 5% was first induced by a low-frequency stimulation (2 Hz) applied for 10 min. After 30 min, theta-burst stimulation was delivered to previously depressed connections, resulting in long-term potentiation (LTP) by 28.8 +/- 11.8%. When theta-burst stimulation was delivered without an earlier low-frequency stimulation, no LTP was induced. Similar results were obtained in layer V connections (LTD: 40.6 +/- 12.5%; LTP: 26.9 +/- 12.5%). In layer IV, the application of 100 micro m d,l-2-amino-5-phosphonovaleric acid (APV), an antagonist of NMDA receptors, blocked the induction of both LTD and LTP. These experiments show that a potential for synaptic plasticity is retained in granular and infragranular layers of adult mice.     

Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices

We previously demonstrated in the dentate gyrus (DG) of anesthetized and freely behaving rats that both acute as well as chronic administration of corticosterone produces a suppression in long-term potentiation (LTP). In subsequent studies we showed, again in the DG, that activation of the two types of adrenal steroid receptors (mineralocorticoid (MR) and glucocorticoid (GR)) produce biphasic effects on synaptic plasticity; activation of MR produces an enhancement while activation of GR produces a suppression in LTP. In a separate study, we further demonstrated in rats administered the specific GR agonist RU 28362 that high-frequency stimulation, which normally produces LTP, instead produced long-term depression (LTD) in these animals. In the present study we investigated the effects of MR and GR activation by adrenal steroids on synaptic plasticity of the hippocampal CA1 field, but we studied this ex vivo, in a slice preparation. The results indicate that, as in our studies in the DG, adrenal steroids produce biphasic effects: in ADX rats, aldosterone (a specific MR agonist) enhanced while RU 28362 suppressed synaptic plasticity. Unlike the in vivo preparation, however, rarely was LTD observed in the animals receiving RU 28362. Also, ADX itself did not produce noticeable effects on synaptic plasticity. The present results are in agreement with previous studies showing that elevations in corticosterone or an acute episode of experimentally induced stress in vivo causes a suppression in LTP in the hippocampal CA1 field, in vitro.