Adenosine (A2) antagonist inhibits induction of long-term potentiation of evoked synaptic potentials but not of the population spike in hippocampal CA1 neurons.

The effects of adenosine A2 receptor antagonist (CP-66713) on long-term potentiation were studied using guinea pig hippocampal slices in a perfusion system. Tetanic stimulation of Schaffer collateral input which was applied during perfusion of CP-66713 (10 microM), did not induce long-term potentiation but rather long-term depression of evoked synaptic potentials (field EPSP), but induced long-term potentiation of the population spike in CA1 neurons. Thus, adenosine derivatives which accumulate in the synaptic cleft during the tetanic stimulation may be involved in induction of the long-term potentiation via A2 receptors at the synapse. The clear discrimination between long-term depression of the field EPSP and long-term potentiation of the population spike suggests EPSP-spike potentiation at the postsynaptic sites.     

Aminoglycoside antibiotics affect hippocampal LTP: a comparative study with the N-type calcium antagonist omega-conotoxin-GVIA.

The in vitro activity of N-type calcium antagonists such as omega-conotoxin-GVIA and the aminoglycoside antibiotics neomycin and streptomycin was studied in rat hippocampal slices. The effects of the drugs were tested on basal CA1 synaptic transmission and on the hippocampal long-term potentiation (LTP) induced by tetanic electrical stimulation and by increasing (4mM) the calcium concentration. Omega-conotoxin-GVIA, neomycin and streptomycin were able to significantly reduce the amplitude of the CA1 population spike at 1 microM, 0.5 mM and 1 mM, respectively. In addition, the drugs affected the induction and maintenance of the CA1 tetanic and calcium-induced LTP at concentrations which did not modify the magnitude of the control CA1 population spike. Omega-conotoxin-GVIA (0.5 microM), neomycin (0.3 mM) and streptomycin (0.7 mM) perfused for 60 min, before inducing LTP, prevented the subsequent increase of the CA1 population spike in all the experiments. The same concentrations of these drugs perfused for 60-min after a previously established LTP significantly reduced the amplitude of the CA1 population spike. The results promote a role for the N-type calcium channels and for the release of neurotransmitters in both the induction and the maintenance of hippocampal LTP.     

The effect of exogenous gangliosides on the dynamics of the development of prolonged posttetanic potentiation]

In hippocampal slices of rats was studied the influence of different gangliosides on the dynamics of development of long-term post-tetanic potentiation (LPTP) in the pyramidal cell layer of the CA3 area at stimulation of the mossy fibers. Each ganglioside was shown to change synaptic efficiency specifically after the tetanic stimulation. Incubation of hippocampal slices with monosialoganglioside GM1 induced the rapid increase of population spike amplitude in the pyramidal neurons being of higher level in comparison to that of the active control up to the end of the experiment. Disialoganglioside GD1b increased the amplitude of the summary cellular response to a lesser degree than GM1, but contributed to its conservation up the control level in the course of the whole recording period. Gangliosides GD1a and GT1b induced inhibitory action on LPTP decreasing population spike value lower than that of both the control and initial levels, GT1b causing more rapid decrease of amplitudes of cellular responses than GD1a. A conclusion was drawn on the participation of gangliosides in the mechanisms of synaptic plasticity. The differential influence of various kinds of gangliosides on the LPTP dynamics was found out. The possible mechanisms of these reactions are discussed.     

Long-lasting potentiation in hippocampus is not due to an increase in glutamate receptors

In transversely sectioned rat hippocampal slices, the effects of low (20 Hz, 600 pulses) and high (400 Hz, 200 pulses) frequency tetani of Schaffer collaterals were examined on the CA1 population spike as well as on the binding of 3H-glutamate. The population spike was suppressed while 3H-glutamate binding greatly enhanced following a low frequency tetanus. Verapamil (1 micron), which does not block long-lasting potentiation (LLP), counteracted the depression of the population spike as well as the associated increase in 3H-glutamate binding. The high frequency tetanus induced LLP of the population spike but caused no change in the amino acid binding. These results indicate that the increase in the number of glutamate receptors is not a requirement for LLP.     

Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices

The presence of polyribosomes in dendritic spines suggests a potential involvement of local protein synthesis in the modification of synapses. Dendritic spine and synapse ultrastructure were compared after low-frequency control or tetanic stimulation in hippocampal slices from postnatal day (P)15 rats. The percentage of spines containing polyribosomes increased from 12% +/- 4% after control stimulation to 39% +/- 4% after tetanic stimulation, with a commensurate loss of polyribosomes from dendritic shafts at 2 hr posttetanus. Postsynaptic densities on spines containing polyribosomes were larger after tetanic stimulation. Local protein synthesis might therefore serve to stabilize stimulation-induced growth of the postsynaptic density. Furthermore, coincident polyribosomes and synapse enlargement might indicate spines that are expressing long-term potentiation induced by tetanic stimulation.     

Mechanism of developing "deprivation" potentiation of population responses of neurons in the CA1 field in hippocampal slices]

In rat hippocampal slices, synaptic transmission from Schaffer collaterals to CA1 neurons was studied by assessment of the effects of cessation of low-frequency testing stimulation to the population spike amplitude. A positive correlation between the duration of the stimulation interruption period (from 10 to 120 min) and the increment of the population spike amplitude (from 30 to 100% above baseline level). The "deprivational" potentiation (DP) offers a property of summation and is able to persist for long (testing was continued up to one hour). Prior induction of the long-term posttetanic potentiation (LPTP) that for 1-3 hours prevents the development of the late rather than the short-term LPTP phase, in our experiments also suppressed the DP induction after 60-min stimulation interruption interval. The same results were obtained in the presence of polymixin B (20 mcM), which is an inhibitor of protein kinase C (PKC) and PKC-dependent phase of the LPTP. This finding provides support for the earlier assumption about the similarity of the mechanisms responsible for the development of the DP and PKC-dependent LPTP phase related with protein phosphorylation.     

2 Hz与100 Hz刺激在诱导大鼠视皮层长持续长时程增强中的不同作用

在哺乳动物的视皮层,多种不同参数的刺激可诱导出长时程增强(long-term potentiation,LTP)现象。但关于刺激参数与持续时间长于3h的长持续LTP(long lasting LTP,L-LTP)之间关系的研究较少。本研究用3周龄的大鼠视皮层脑片标本,在Ⅳ层刺激而在Ⅱ／Ⅲ层记录场电位,待场电位稳定后施加强直刺激诱导LTP,探讨2Hz与100Hz的强直刺激在诱发持续时间长于3h的L-LTP中的作用。结果表明,多于300个脉冲不同频率的刺激可稳定地诱导出L-LTP;2Hz与100Hz的刺激诱发的L-LTP有明显不同的表达形式,100Hz刺激可诱导出较大的L-LTP;频率相同而脉冲数不同的强直刺激诱发的L-LTP有相同的表达形式。以上结果提示,不同频率的强直刺激诱发的L-LTP机制可能不同;相同频率的刺激(脉冲数不同)诱发的L-LTP可能有相同的机制。     

Medial septal region as a target for modulation of seizure discharges in the hippocampus in a model of acute temporal lobe epilepsy

Investigation of changes in the hippocampal EEG produced by GABAergic and cholinergic substances delivered into the medial septum region was performed in awake rabbits. Changes in the threshold of seizure discharges in the hippocampus evoked by perforant path stimulation (model of acute epilepsy) were also examined. Injections of GABAA receptor antagonist picrotoxin or agonist of cholinergic receptors carbacholine in low doses induced an increase in the power of delta- and theta modulation and appearance of 7-12-Hz oscillations. The threshold of hippocampal seizure afterdischarges decreased. In higher doses, these substances evoked 7-15-Hz oscillations followed by seizures. GABAA receptor agonist muscimol and muscarinic receptor antagonist scopolamine decreased the power of the theta rhythm and increased the seizure threshold. Picrotoxin or carbacholine injected after muscimol or scopolamine, respectively, did not evoke seizures. Thus, we have shown the possibility to control hippocampal activity by local changes in the GABAergic and cholinergic systems of the medial septum region.     

Verapamil counteracts the masking of long-lasting potentiation of hippocampal population spike produced by 2-amino-5-phosphonovalerate

In transversely sectioned rat hippocampal slices the effects of 2-amino-5-phosphonovalerate (APV), presumably a selective N-methyl-DL-aspartate antagonist, were examined on the development of long-lasting potentiation (LLP) of the CA1 population spike produced by Schaffer collateral tetanization (100 Hz, 1 s). APF (100 nA, 5 min), when applied 150-200 micron away from the CA1 cell bodies (apical dendritic area), had no significant effect if the population spike was evoked at 0.1 Hz, but produced a depression of the population spike if a 100 Hz tetanus was given during its iontophoresis. This depressant effect of APV was counteracted by verapamil (0.33 microM, 3 min) and LLP induced by the 100 Hz tetanus was unmasked. It is suggested that APV does not antagonize LLP, but only masks it by allowing CA++ influx into CA1 neurones that induces a depression. The results also raise doubts as to the selectivity of APV as an amino acid antagonist.     

Verapamil counteracts depression but not long-lasting potentiation of the hippocampal population spike

In transversely sectioned rat hippocampal slices, population spikes and population "EPSPs" were recorded from CA1 neurones in response to the stimulation of Schaffer collateral and commissural inputs. High frequency tetanic stimulation (400 Hz, 200 pulses) of an input induced LLP of the homosynaptic response without significantly changing the heterosynaptic response. This LLP was not interrupted by either a 400 Hz tetanus given to the heterosynaptic input or by verapamil (0.33 microM) which blocks Ca++ channels, but not transmitter release. A low frequency tetanus (20 Hz, 200 pulses) given to an input induces co-occurring homosynaptic and heterosynaptic depressions of about 20 min duration. This tetanus could also mask an established LLP in homosynaptic or heterosynaptic pathway. Verapamil counteracts homo- and heterosynaptic depressions. The population spike as well as the population "EPSP" were depressed following iontophoretic application of Ca++ (2-100 nA) at the CA1 cell body area. These results indicate that homosynaptic and heterosynaptic depressions are at least partly due to an accumulation of Ca++ into CA1 neurones. An established LLP is not interrupted by LLP of another input. Homo- and heterosynaptic depressions mask, but not reverse, LLP.     

Characteristics of tetanic and post-tetanic potentiation in the septohippocampal and hippocampal commissural systems in the acute rabbit

The frequency characteristics of tetanic and post-tetanic potentiation of the septohippocampal and hippocampal commissural systems were studied in the acute rabbit preparation. Glass micropipettes were employed to stimulate the medial septal (MSR) and contralateral CA1 (cCA1) regions. Extracellular postsynaptic potentials were recorded in the stratum radiatum and stratum oriens layers of dorsal CA1. Low frequencies of stimulation (2–12 Hz) and brief stimulus trains (7 or 16 stimuli) ensured that only short-term effects appeared in the data. With MSR and cCA1 stimulation, tetanic potentiation became pronounced at 4 Hz, and plateaued at 6–8 Hz. Thus potentiation was found to be pronounced within the range of the rabbit hippocampal theta rhythm. No differences were found in the characteristics of potentiation evoked by stimulation of MSR and cCA1. Post-tetanic potentiation lasting 6–12 sec was found. Again, potentiation characteristics did not depend on stimulus site, suggesting a common mechanism for the pathways studied. A two-factor mechanism was proposed to account for the post-tetanic potentiation data.     

Modulation of learning and hippocampal, neuronal plasticity by repetitive transcranial magnetic stimulation (rTMS)

The influence of high-frequency repetitive transcranial magnetic stimulation (rTMS) on learning process in mice and on neuronal excitability of the hippocampal tissue obtained from stimulated animals were investigated. While the stimulation with rTMS at higher frequency (15 Hz) improved animals' performance in novel object recognition test (NOR), lower frequency (1 and 8 Hz) impaired the memory. The effect was observed when evaluated immediately after rTMS exposure and declined with time. In parallel to the results of behavioral test, there was a significant enhancement of the synaptic efficiency expressed as of the long-term potentiation (LTP) recorded from hippocampal slices prepared from the animals exposed to 15 Hz rTMS. The stimulation with 1 and 8 Hz had no influence on the magnitude of LTP. Our results demonstrate that rTMS modifies mechanisms involved in memory formation. The effects of rTMS in vivo are preserved and expressed in the hippocampus tested in vitro.     

The long-term potentiation of the late NMDA-dependent components of the responses of the cat motor cortex neurons to stimulation of the direct cortical input of area 5 in the parietal cortex]

Activity of neurons in the motor cortex was recorded in anesthetized cats with glass micropipettes filled with bicuculline solution (bicuculline methiodide, 10 mM in 1 M NaCl). Under these conditions, the minimal (near-threshold) electrical stimulation of the area 5 of the parietal cortex evoked the late neuronal discharges (in 30-200-ms poststimulus interval) in the motor cortex. Such discharges resembled the late NMDA-dependent discharges recorded in the motor cortex of awake cats in response to stimulation of the parietal cortex, which produced the preliminary elaborated conditioned forepaw placing. Under the same conditions, tetanic stimulation of the parietal cortex (100 Hz, 10-20s) led to the long-term potentiation of the late response, which manifested itself as response amplitude augmentation and latency shortening.     

Role of EGR1 in hippocampal synaptic enhancement induced by tetanic stimulation and amputation

Hippocampal neurons fire spikes when an animal is at a particular location or performs certain behaviors in a particular place, providing a cellular basis for hippocampal involvement in spatial learning and memory. In a natural environment, spatial memory is often associated with potentially dangerous sensory experiences such as noxious or painful stimuli. The central sites for such pain-associated memory or plasticity have not been identified. Here we present evidence that excitatory glutamatergic synapses within the CA1 region of the hippocampus may play a role in storing pain-related information. Peripheral noxious stimulation induced excitatory postsynaptic potentials (EPSPs) in CA1 pyramidal cells in anesthetized animals. Tissue/nerve injury caused a rapid increase in the level of the immediate-early gene product Egr1 (also called NGFI-A, Krox24, or zif/268) in hippocampal CA1 neurons. In parallel, synaptic potentiation induced by a single tetanic stimulation (100 Hz for 1 s) was enhanced after the injury. This enhancement of synaptic potentiation was absent in mice lacking Egr1. Our data suggest that Egr1 may act as an important regulator of pain-related synaptic plasticity within the hippocampus.     

Effects of low-frequency tetanic stimulation of the synaptic inputs on different forms of long-term potentiation in the rat hippocampus

In experiments on transversal slices of the dorsal hippocampus of rats, we found that low-frequency stimulation of the mossy fibers (MF) against the background of pre-settled long-term post-tetanic potentiation in the MF-CA3 pyramidal neuron (PN) dendrites synaptic system evoked depotentiation in all studied slices. Depotentiation was considerably decreased by a non-competitive blocker of the NMDA glutamate receptors, ketamine (100 μM), as well as by an inhibitor of calmodulin, trifluoroperazine (10 μM), and an inhibitor of calcineurin, cyclosporin A (250 μM). At the same time, depontentiation was not changed by 50 μM polymixin B, an inhibitor of protein kinase C. Long-term potentiation of synaptic transmission in the Schaffer collaterals (SchC)-CA1 PN dendrites system, which was evoked by 2.5-min-long anoxia/aglycemia episodes, resulted exclusively from enhancement of the NMDA component of population EPSP, while their AMPA component was not modified, i.e., in this case potentiation was of a postsynaptic nature. Under these conditions, low-frequency stimulation of SchC resulted in a further increase in the intensity of synaptic transmission due to increases in both the NMDA and AMPA components of population EPSP. The above form of potentiation could be suppressed by 100 μM ketamine, 10 μM trifuoroperazine, 250 μM cyclosporin A, or 10 μM N-nitro-L-arginine. Weak (near-threshold) high-frequency stimulation of SchC induced long-lasting potentiation of synaptic transmission due to an isolated increase in the AMPA component of population EPSP, i.e., this potentiation was of a postsynaptic nature. In the latter case, low-frequency SchC stimulation resulted in further facilitation of synaptic transmission. Intensive tetanic high-frequency stimulation of the above fibers induced long-term potentiation of a presynaptic nature, while their low-frequency stimulation depotentiated synaptic transmission.     

Long-term changes in EEG spectra of the hippocampus and neocortex during pharmacological action on the cholinergic system

Statistical analysis of EEG spectra averaged over 10-min periods showed that inhibitor of acetylcholinesterase physostigmine induced the long-term (tens of minutes) characteristic changes in the electric activity of the dorsal hippocampus (CA1 field) and somatosensory cortex of unrestrained rats. With increasing the physostigmine dose from 0.05 to 0.5 or 1 mg/kg the averaged power of the theta-rhythm did not rise in the range of 3.6-4.9 Hz and was suppressed in the range of 5.7-11.9 Hz both in the hippocampus and neocortex. The maximal frequency shifted to the left (from 3.6-6.4 to 3.6-4.9 Hz). In contrast to this, the averaged power in the delta (1-1.5 Hz)-I and beta-2 ranges (20.3-26.5 Hz) significantly nonlinearly increased and that of the beta-1 substantially decreased. Scopolamine eliminated all extrema of the hippocampal and neocortical EEG spectra induced by physostigmine, which is indicative of the role of M-cholinoreceptors in these effects. The increased dose of physostigmine (1 mg/kg) produced inversion of the ratio between the averaged power of beta-2 in neocortex and hippocampus: it became significantly higher than in the neocortex. All these data suggest that the mechanisms of cholinergic modulation of the theta- and beta-rhythms are essentially different. We think that significant enhancement of the content of endogenous acetylcholine content produce a long-term tonic decay of the functional activity of the hippocampus and neocortex and play an important role in the mechanisms of dissociated states of memory and consciousness, contextual learning and conditioned switching.     

Effects of Chronic Stress and Phenytoin on the Long-term Potentiation （LTP） in Rat Hippocampal CA1 Region

Stress is the response to stimulation from inside andoutside with complicated effects on organisms. Appropri-ate stressful reactions are helpful in resisting diseases byactivating unspecific modulation system, while severe orprolonged stresses are harmful and even induce mentaland physical disorders such as recurrent depression, post-traumatic stress disorder (PTSD), Alzheimer’s disease andepilepsy [1]. Hippocampus, a main brain region of keyimportance for learning, memory and emotion, is t…     

Effects of adrenal steroids and their reduced metabolites on hippocampal long-term potentiation

We studied the effects of steroid hormones on the hippocampal long-term potentiation (LTP), a putative mechanism of neuronal plasticity and memory storage in the CNS. In vivo experiments were performed in rats under chloral hydrate anesthesia (0.4 mg/kg i.p.). All animals were adrenalectomized 48 h before recording. LTP was induced after priming tetanic stimulation at the perforant pathway (PP) and single pulse field potentials were obtained from the dentate gyrus (DG). The excitatory post-synaptic potential (EPSP) slope and population spike (PS) amplitude were analyzed before and after the i.v. injection of the steroids and after the induction of LTP, and followed up to 1 h. Results obtained with the hormones were compared with matched control animals injected with vehicle alone, Nutralipid 10%. Previous results from our laboratory showed that deoxycorticosterone (DOC) decreased the magnitude of the EPSP at all times after priming stimulation and the PS decreased during the first 30 min of the LTP. Corticosterone decreased the EPSP in the first 15 min and the PS during the first 30 min after priming stimuli. In these experiments the mineralocorticoids aldosterone and 18-OH-DOC elicited a decrease of the EPSP at all times post-train; and no significant difference against vehicle was observed in the PS. Post-injection values were not changed except for 18-OH-DOC at a dose of 1 mg, where a decrease of both the EPSP (P less than 0.01) and the PS (P less than 0.02) was observed against vehicle. ATH-progesterone at 0.1 mg/rat also decreased the EPSP values significantly after priming stimulation and no significant changes against vehicle were observed in the PS. These results show that adrenal steroids can modulate hippocampal LTP, that they can act at different neuronal loci and with different time courses in the development of the phenomena.     

Enhanced Sensitivity of "Metabotropic" Glutamate Receptors After Induction of Long-Term Potentiation in Rat Hippocampus

Stimulation of [3H]inositol monophosphate ([3H]InsP) formation by ibotenate or trans-1-aminocyclopentyl-1,3-dicarboxylic acid (t-ACPD) in rat hippocampal slices was enhanced after tetanic stimulation of the Schaffer collaterals projecting to the CA1 region (in vitro) or the perforant pathway projecting to the dentate gyrus (in freely moving animals). This effect was observed 5 h (but not 2 h) after long-term potentiation (LTP) induction and was abolished if tetanic stimulation was performed in the presence of specific antagonists of N-methyl-D-aspartate receptors. The delayed increase in excitatory amino acid-induced polyphosphoinositide (PPI) hydrolysis was accompanied by an enhanced responsiveness to norepinephrine, whereas the basal and carbamylcholine-stimulated [3H]InsP formation were unchanged. These results suggest that an increased activity of "metabotropic" glutamate receptors may contribute to the synaptic mechanisms enabling the late expression and or maintenance of LTP. Accordingly, LTP decayed more rapidly (within 5 h) in rats repeatedly injected with LiCl (60-120 mg/kg, i.p., for 10 days), a treatment that led to a reduced efficacy of ibotenate and norepinephrine in stimulating PPI hydrolysis in hippocampal slices.