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.     

Effects of A1 and A2 Adenosine Receptor Antagonists on the Induction and Reversal of Long-Term Potentiation in Guinea Pig Hippocampal Slices of CA1 Neurons

1. Using simultaneous recordings of the field EPSP and the population spike in the CA1 neurons of guinea pig hippocampal slices, we confirmed that delivery of a high-frequency stimulation (tetanus: 100 pulses at 100 Hz) produced robust long-term potentiation of synaptic efficacy (LTP) in two independent components, a synaptic component that increases field excitatory postsynaptic potentials (EPSPs) and a component that results in a larger population spike amplitude for a given EPSP size (E-S potentiation).2. In the same cells, reversal of LTP (depotentiation; DP) in the field EPSP and in the E-S component is achieved by delivering low-frequency afferent stimulation (LFS:1 Hz, 1000 pulses) 20 min after the tetanus.3. When the tetanus or LFS was applied to CA1 inputs in the presence of an adenosine A₁ receptor antagonist, 8-cyclopentyltheophylline (1 M), the field EPSP was enhances in LTP and attenuated in DP, while the E-S relationship was not significantly affected in either LTP or DP.4. When similar experiments were performed using an A₂ receptor antagonist, CP-66713 (10 M), the field EPSP was blocked in LTP but facilitated in DP, while E-S potentiation was enhanced during both LTP and DP.5. The results show that endogenous adenosine, acting via A₁ or A₂ receptors, modulates both the synaptic and the E-S components of the induction and reversal of LTP. Based on the results, we discuss the key issue of the contribution of these receptors to the dynamics of neuronal plasticity modification in hippocampal CA1 neurons.     

Long-Term Posttetanic Changes of Synaptic Transmission and Synapse Morphology of the Pike <Emphasis Type="Italic">Esox lucius</Emphasis> Olfactory Bulb

In the olfactory bulb (OB) of the pike, phenomena of long posttetanic potentiation (LPTP) and long posttetanic depression (LPTD) are reproduced. Probability of induction of LPTP and level of its expression are shown to depend direct on parameters of density of axo-dendritic synapses in the glomerular neuropil and size of its active zones (AZ). In pikes with the high level of these parameters (the synapse density 5.2 per 20 µm², the mean length of AZ cross-section 293 nm), potentiation appear in 95% of cases, while in pikes with low values (the density 3.1, the AZ length 239 nm) in as low as 30%, with LPTD developing rather often instead of LPTP. The LPTP in the phase of its maximal development (60 min after tetanus) corresponds to an increase of the mean length of AZ cross-section of axodendritic synapses by 13.6%, while the LPTD—to its decrease by 16.5% as compared with control. The LPTP induction phase (5–15 min after tetanus) is not associated with any ultrastructural transformations of postsynaptic AZ of axo-dendritic synapses. By the morphometric method, it has been established that LPTP in the pike OB is of the homosynaptic nature, i.e., is due to an enhancement of synaptic efficiency of the excitatory afferent input just subjected to tetanization. On the whole, by using axo-dendritic synapses of the pike OB as an example it was shown that in simple, flat, asymmetric excitatory synapses a steady enhancement of their effectiveness was accompanied by an increase of length of AZ cross-sections, while a reduction of their efficiency—by its decrease.__________Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 3, 2005, pp. 285–292.Original Russian Text Copyright © 2005 by Ruzhinskaya, Gdovskii.     

Effects of physostigmine and scopolamine on long-term potentiation of hippocampal population spikes in rats

To elucidate an involvement of the cholinergic system in the long-term potentiation phenomenon, effects of physostigmine and scopolamine on population spike and its long-term potentiation in the dentate granule cell layer of anesthetized rats and in the CA1 pyramidal cell layer of rat hippocampal slices were examined. In anesthetized rats, physostigmine (0.01 mg/kg, i.v.) enhanced at a late phase the long-term potentiation induced by tetanic stimulation (15 Hz, 15 s, 7.5 times the threshold for population spike) of the perforant path, while scopolamine (1.0 mg/kg) suppressed it at an early phase. The two drugs did not affect the population spike itself. The time course of the long-term potentiation under the treatment of physostigmine was similar to that induced by stronger tetanic stimulation (10 times the threshold). In hippocampal slices, physostigmine (10(-6)M) showed a tendency to enhance the long-term potentiation induced by tetanic stimulation (15 Hz, 15 s, 5 times the threshold) of the stratum radiatum, with an increase of the population spike itself. Scopolamine (10(-5)M) markedly suppressed the long-term potentiation with a decrease of the population spike itself. From these results, it is suggested that cholinergic modification by physostigmine or scopolamine affects the long-term potentiation phenomenon in the hippocampus under the in vivo and in vitro conditions.     

Long-term potentiation and unit evoked responses in the cingulate cortex of freely moving rats

Long-term potentiation (LTP) of synaptic efficacy is considered to be the most probable physiological mechanism of long-term memory. However, lack of understanding of cellular and subcellular mechanisms of LTP induction in freely behaving animals does not correspond to the importance of the problem. It was tested whether the characteristics of potentiation in the cingulate cortex after tetanization of the subiculocingulate tract (SCT) meet the criteria of true LTP (that passes all known stages in its development and lasts for more than a day in freely-behaving animals). Additionally, characteristics of spike responses to SCT stimulation and the effects of application of different glutamate receptor blockers were studied. Without application of GABA receptor blockers, the LTP lasted for more than 24 hours. Application of NMDA glutamate receptor blockers significantly inhibited field potentials evoke by testing stimulation. Short-latency spike responses to SCT stimulation were recorded with low probability that increased with stimulation intensity. The obtained data reveal the possibility to compare the involvement of cingulate neurons in acquisition of adaptive behavior and changes in their spike responses during the LTP development in freely-moving rats.     

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.     

Effects of extracellular calcium on low frequency induced potentiation and habituation in the in vitro hippocampal slice preparation

The electrophysiological characteristics of frequency potentiation and habituation were investigated in two afferent systems of the in vitro hippocampal slice preparation. Low frequency stimulation (1 Hz) of the Schaffer collateral - commissural (Sch-comm) fibers results in a short-term potentiation of the amplitude and rate of rise of the EPSP and population spike responses recorded in the CA1 region. In contrast, 1-Hz stimulation of the perforant path (PP) evokes a short-term, habituation-like depression of the dentate granule cell EPSP and population spike. An inverse relationship was observed between stimulus intensity and the magnitude of frequency potentiation or habituation. Changes in afferent fiber volleys or general excitability of postsynaptic membranes did not contribute significantly to the development of either of these forms of short-term plasticity. Perfusion with a medium containing a high calcium - low magnesium concentration (4 mM Ca+2 and 1 mM Mg+2) produced a differential effect on CA1 and dentate evoked potentials. Following a 20-min exposure to this medium, the amplitude of CA1 potentials was increased while dentate responses were decreased. Frequency potentiation of CA1 responses and habituation of dentate responses were depressed or eliminated by the high calcium medium. The opposing influence of extracellular calcium on CA1 and dentate evoked potentials indicates a fundamental difference in the process of transmitter release in these systems, a characteristic that may contribute to the production of frequency potentiation and habituation.     

Conditions required for appearance of a double response to a single-shock stimulation of Schaffer collaterals in hippocampal field CA1 in freely moving rats

Schaffer collateral stimulation with a single current impulse can evoke a double response in hippocampal field CA1 of freely moving rats. The late response appears as a population excitatory postsynaptic potential with a preceding short-term potential (frequently biphasic) only after the early population spike and is time-locked to it. The wave shape and polarity of the late response, its latency with respect to the peak of the early population spike suggest that the excitation wave produced in the CA1 field by the stimulation of Schaffer collaterals passes across the entorhinal cortex and returns to the CA1 directly via the perforant path fibers. In waking rat, the medium-intensity stimulation of Schaffer collaterals (able to evoke in the CA1 an early population spike of sufficiently high amplitude) usually does not result in the appearance of the late response. However, similar stimulation becomes efficient after the tetanization of Schaffer collaterals, under conditions of the long-term potentiation of the early population spike. Moreover, the late response occurrence is facilitated in a rat falling asleep after the development in the CA1 of high-amplitude low-frequency EEG oscillations typical for the slow-wave sleep and in a sleeping rat independently of the EEG pattern.     

Temperature dependence of synaptic responses in guinea pig hippocampal CA1 neurons in vitro

1. Temperature-dependent properties of synaptic transmission were studied by recording orthodromic responses of the population spike and excitatory postsynaptic potential in CA1 pyramidal neurons of guinea pig hippocampal slices.2. Increasing the temperature of the perfusing medium from 30 to 43°C resulted in a decrease in the amplitude of the population spike (A-PS) and a reduced slope of the excitatory postsynaptic potential (S-EPSP). Bath application of the -aminobutyric acid receptor antagonist, picrotoxin, or a change in the calcium concentration of the perfusate did not affect the A-PS during heating.3. Increasing the strength of the synaptic input to that eliciting a PS with an amplitude 50, 75, or 100% of maximal at 30°C resulted in a significant increase in the A-PS during the middle phase of hyperthermia (35–39°C).4. The long-term potentiation (LTP) induced at either 30 or 37°C showed the same percentage increase in both the amplitude of the population spike and the S-EPSP after delivery of a tetanus (100 Hz, 100 pulses) to CA1 synapses.5. The results of the present study, therefore, indicate that the decrease in CA1 field potential was linearly related to the temperature of the slice preparation, while LTP was induced in these responses during heating from 30 to 37°C.     

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…     

Correlated activity of neurons in the sensorimotor cortex of rabbits in the state of defensive dominanta and "animal hypnosis"

A hidden excitation focus (dominanta focus) was produced in the rabbit's CNS by threshold electrical stimulation of the left forelimb with the frequency of 0.5 Hz. As a rule, after the formation of the focus, pairs of neurons with prevailing two-second rhythm in their correlated activity were revealed both in the left and right sensorimotor cortices (with equal probabilities 29.3 and 32.4%, respectively). After "animal hypnosis" induction, the total percent of neuronal pairs with the prevalent dominanta-induced rhythm decreased significantly only in the right hemisphere (21%). After the termination of the "animal hypnosis" state, percent of neuronal pairs in the right cortex with prevailing two-second rhythm significantly increasead if the neurons in a pair were neighboring and decreased if they were remote from each other. Similar changes after the hypnotization were not found in the left cortex. Analysis of correlated activity of neuronal pairs with regard to amplitude characteristics showed that for both the right and left hemispheres, the prevalence of the two-second rhythm was more frequently observed in crosscorrelation histograms constructed regarding discharges of neurons with the lowest spike amplitude (in the right hemisphere) or the lowest and mean amplitudes (in the left hemisphere) selected from multiunit records.     

Heparin suppresses specific second messenger pathways for protooncogene expression in rat vascular smooth muscle cells.

We investigated the molecular mechanisms underlying the ability of heparin to inhibit vascular smooth muscle cell (VSMC) growth. Previous experiments have shown that heparin inhibits induction of c-fos and c-myc protooncogene mRNA in rat VSMC stimulated by phorbol 12-myristate 13-acetate (PMA) but not when stimulated by epidermal growth factor (EGF) (Pukac, L. A., Castellot, J. J., Wright, T. C., Caleb, B. L., and Karnovsky, M. J. (1990) Cell Regul. 1, 435-443). The present experiments show that these mitogens activate distinct second messenger pathways in VSMC, because PMA but not EGF induction of c-fos and c-myc mRNA was suppressed in protein kinase C (PKC) down-regulated VSMC; this suggests that EGF does not act through a PKC-dependent pathway for induction of these genes. Heparin inhibited serum stimulation of c-fos mRNA in control VSMC, but heparin did not inhibit the smaller but significant serum stimulation of c-fos mRNA in PKC down-regulated VSMC, indicating that heparin may selectively inhibit PKC-dependent, but not PKC-independent, stimulation of gene expression. To further determine if heparin inhibits non-PKC pathways, VSMC were treated with dibutyryl cAMP, 3-isobutyl-1-methyl-xanthine, and Ca2+ ionophore A23187; stimulation of c-fos mRNA by this treatment was not inhibited by heparin. DNA synthesis and cell proliferation were inhibited in rat VSMC exposed briefly to heparin during the G0/G1 phase of the cell cycle. These experiments indicate heparin can act early in the cell cycle and suggest PKC-dependent but not PKC-independent signaling pathways for gene expression are selectively sensitive to heparin inhibition.     

The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses

In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr⁷⁵, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.     

Postsynaptic mechanisms of induction of NMDA-dependent long-term post-tetanic potentiation of synaptic transmission

Experiments on hippocampus slices of rats showed that the pattern of induction of long-term post-tetanic potentiation of synaptic transmission is determined by the frequency of tetanic stimulation of Schaffer collaterals. With their high-frequency (>10/sec) stimulation, a phase of reversible increase in the amplitude of population EPSP (pEPSP) is observed within the initial 30-min-long interval; it is related to an increase in the intracellular Ca²⁺ concentration resulting from simultaneous activation of NMDA and metabotropic glutamate receptors and voltage-activated calcium channels. With the participation of calmodulin, Ca²⁺ activate Ca²⁺-calmodulin-dependent protein kinase II. The latter phosphorylates AMPA/kainate receptors (their kainate-responsive compartments), which promotes an increase in their chemosensitivity. Under conditions of low-frequency (<10/sec) tetanic stimulation of synaptic inputs, for the same reasons, an increase in the intradendritic Ca²⁺ concentration exerts no expressed influence on protein kinase II, but activates calcineurin. The latter, with the involvement of other phosphoprotein phosphatases, dephosphorylates AMPA/kainate receptors and turns some of them into the refractory state; this is expressed in a reversible depression of pEPSP. After 30 min of either high-frequency, or low-frequency stimulation, a non-decremental phase of long-term post-tetanic potentiation develops, which is related to the increase in the protein kinase C activity, phosphorylation of the AMPA-responsible compartments of AMPA/kainate receptors, their rising sensitivity, and a stable increase in the pEPSP amplitudeNeirofiziologiya/Neurophysiology, Vol. 28, No. 4/5, pp. 163–172, July–October, 1996.     

Neuronal transmission of hippocampal CA1 neurones is modulated by corticotropin-like intermediate lobe peptide [CLIP; ACTH(18–39)]

The study was conducted to test whether CLIP [ACTH(18–39)] influences the neuronal transmission and the induction of longterm potentiation (LTP) in the hippocampus. The population spike was recorded in the hippocampal CA1 region of freely moving rats before and after intracerebroventricular (ICV) administration of CLIP in comparison to ACTH and saline (controls). After infusion of CLIP, the population spike amplitude (PSA) rose to about 200% of baseline values. After reaching this level, it was impossible to induce a further increase of PSA by tetanization. However, if the stimulus intensity was reduced to a new baseline level, electrically induced LTP could be observed. There were no significant changes after infusion of ACTH. Our results indicate that the ICV administration of CLIP leads to an enhancement of excitability in the hippocampal CA1 region, which might be independent of LTP.     

C-Type natriuretic peptide modulates pre- and postsynaptic properties in hippocampal area CA1 in vitro

The cGMP producing natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP) are widely distributed in the brain and are highly expressed in the hippocampal regions CA1-CA3. To date only limited functional data is available concerning the physiological effects of the peptide hormone in the hippocampus. Therefore, we were interested in how bath application of the peptide hormone might influence synaptic plasticity following high frequency stimulation (HFS). We found that CNP application decreased the population spike (PS) amplitude after HFS, thereby affecting long-term potentiation (LTP) in acute hippocampal slices. To investigate the molecular consequences of CNP application leading to a decrease in PS amplitude, we further analyzed the impact of the hormone on the number of presynaptic synapsin I clusters and number of postsynaptic AMPA receptor subunit GluR1 clusters as well as their co-localization in a primary hippocampal cell culture system. The observed pre-and postsynaptic effects after CNP stimulation of the cGMP pathway in hippocampal cell cultures may underlie the effect of the peptide hormone on LTP.     

Modulation of the thalamocortical responses of the sensorimotor cortex during stimulation of the lateral hypothalamus in rabbits in ontogeny

It has been demonstrated that rhythmic stimulation of the relay thalamic nucleus in rabbits at the second half of the first month of postnatal life does not significantly affect the amplitude of the second and third positive components (PC-2 and PC-3) of the positive phase of the thalamocortical responses. Combination of rhythmic stimulation of this nucleus and that of lateral hypothalamic structures is accompanied by a significant increase of the amplitude of both positive components of the thalamocortical responses, the degree of potentiation of PC-3 being higher than that of PC-2. The described potentiation is most evident at the third week of postnatal development of rabbits.     

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.     

Spike amplitude modulation at high stimulation frequencies

Summary A technique of mathematical analysis has been developed for studying spike amplitude variations, during natural sinusoidal stimulation. This technique is suitable even when stimulation frequency is of the same order as, or higher than, the cell firing rate.We used this technique for the cat's retinal ganglion cells. The results agree with the previous ones (Gestri et al., 1967) at low stimulation frequencies and show that the spike amplitude modulation occur even at high frequencies, the phase shift between spike amplitude and firing probability being a function of the stimulation frequency.