Long-term potentiation of the AMPA and NMDA components of minimal postsynaptic currents in rat hippocampal field Ca1.

The aim of the present work was to study the potentiation of the AMPA and NMDA components of minimal excitatory postsynaptic currents (EPSC) evoked by activation of restricted numbers of synapses. EPSC of neurons in field CA1 in hippocampal slices were recorded in whole-call patch-clamp conditions selected such that both (AMPA and NMDA) components were present, and these were measured in parallel using computational methods in combination with pharmacological receptor blockade. There was a quite strong correlation between the amplitudes of the AMPA and NMDA components and this was regarded as evidence that they were generated by the same synapses. In cases producing this correlation, both components showed essentially equal long-term potentiation lasting from 5 min to 2 h after afferent tetanization. The data did not support the postsynaptic hypothesis and were in better agreement with the concept that the major mechanism for the persistence of the initial phase of long-term potentiation (up to 1-2 h) is based on increases in the quantity of transmitter released presynaptically.

[Long-term potentiation of AMPA- and NMDA-components of minimal postsynaptic currents in CA1 area of the rat hippocampus]. / Dolgovremennaia potentsiatsiia AMPA- i NMDA-komponent minimal'nykh postsinapticheskikh tokov v oblasti CA1 gippokampa krys.

Excitatory postsynaptic currents (EPSC) were recorded from pyramidal neurons of the rat hippocampal slices as well as the AMPA and NMDA components. A strong enough correlation between the amplitudes of the components provided a reliable evidence of their generation by the same synapse. Both components revealed similar LTP following afferent tetanisation. The data obtained do not support postsynaptic mechanisms of the LTP maintenance but suggest that increased presynaptic release represents a basic mechanism of the early LTP maintenance.

[Modulation of NMDA-receptor efficiency by intracellular agents]. / Moduliatsiia éffektivnosti NMDA-retseptorov vnutrikletochnymi agentami.

Glutamate in one of the principle transmitters in the CNS. Ionotropic receptors of glutamate selectively activated by N-methyl-d-aspartate (NMDA) play an important role in the processes of development, learning, memory etc. Hyperactivation of these receptors is responsible for a number of pathological processes. Due to their importance, the NMDA receptors are subjected to strong modulatory influences of different modulatory systems of the brain. Modulation of the NMDA receptor efficiency by extracellular factors is well known and described in a number of reviews, while their modulation by intracellular factors is less known and has not yet been reviewed. This review presents the experimental data concerning a modulatory control of the NMDA receptors by intracellular factors. Some of these factors are: phosphorylation by protein kinases (PK) C, A, Ca2+/calmodulin-dependent PK II, tyrosine kinases; dephosphorylation by protein phosphatases 1, 2A, 2B; interaction with regulatory peptides and cytoskeleton; influence of surrounding lipids etc. Interaction between these factors creates a labile intracellular system, which efficiently modulates activity of the NMDA receptors mediating the activity of different extracellular active compounds (neurotransmitters, neurotoxins, drugs etc.). A cheme summarizing different intracellular pathways of modulation of the NMDA receptor efficiency is described.

Selective suppression of forward and recurrent "rapid" inhibition by local application of picrotoxin in area CA1 of rat hippocampal slices.

Living slices of rat hippocampus were used to study the possibility of suppressing forward and recurrent "rapid" inhibition in area CA1 by local application of picrotoxin, an antagonist of ionotropic gamma-aminobutyric acid (GABAA) receptors. Application of picrotoxin to the apical dendrites increased the duration of focal potentials recorded in the radial layer (143.0 +/- 7.5%, n = 5; here and subsequently, results are presented as mean +/- error of the mean and n is the number of experiments) but had no effect on the population peak in the pyramidal layer (103.0 +/- 19.6%, n = 5). This is evidence for the existence of suppression of direct, but not of recurrent inhibition. Application of picrotoxin to the cell body layer, on the other hand, significantly increased the population peak (654.5 +/- 245.1%, n = 4) and provoked convulsive activity in neurons, demonstrating suppression of recurrent inhibition. Local application of picrotoxin was further used to study the question of how completely antagonists of glutamate ionotropic receptors sensitive to alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) suppress inhibition in solutions with low magnesium contents. This question is important for interpreting experimental data obtained from measurements of the components of excitatory postsynaptic potentials (EPSP), which depend on activation of ionotropic glutamate receptors sensitive to N-methyl-d-aspartic acid (NMDA). A number of studies have suggested that even at low concentrations, AMPA receptor antagonists suppress forward inhibition to such an extent that it has no significant effect on measurements of the NMDA component of EPSP. Our data do not contradict this suggestion.

Synaptic plasticity in the hippocampus during afferent activation reproducing the pattern of the theta rhythm (theta plasticity).

This review summarizes data on the plasticity of hippocampal synaptic pathways in conditions of afferent activation modeling the electrical activity of neurons during the theta rhythm. Activation with short trains of stimuli with frequencies of about 5 Hz efficiently induces long-term potentiation, i.e., stable facilitation of synaptic transmission. Contrarily, single stimuli presented at the same frequency "depotentiate" synapses or even induce long-term depression. Combined theta activity at two synaptic inputs, in phase with each other, induces long-term potentiation, while combined activity in antiphase produces long-term depression of the weakly-activated input (associative long-term potentiation and depression). Short trains of single stimuli at a frequency of 5 Hz induce heterosynaptic short-term depression: the efficiency of all synaptic inputs is decreased for time periods of the order of 1 min. Apart from changes in synaptic efficiency, theta activation affects the ability to induce synaptic rearrangements in conditions of subsequent afferent activation ("cryptic" plasticity). Thus, virtually all known types of synaptic plasticity are efficiently induced by afferent activation of the pattern of the hippocampal theta rhythm, which suggests the possible mechanisms for its roles in learning and memory processes.

Reciprocal inhibition of the AMPA and NMDA components of excitatory postsynaptic potentials in field CA1 of the rat hippocampus in vitro.

The mutual effects of components of excitatory postsynaptic potentials (EPSP) induced by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) were studied on living slices of rat hippocampus. Evoked responses were recorded in the radial layer (stratum radialis) in field CA1 after stimulation of collateral-commissural fibers. The contribution of the NMDA component to the total EPSP was altered by extracellular application of solutions containing different concentrations of magnesium. At low magnesium concentrations, when both components made significant contributions to EPSP, inhibition of one of the components by application of antagonists of the appropriate receptors led to increases in the area of the other component. Thus, the total magnitude of pharmacologically isolated components were significantly greater than the control response (for example, at 0.1 mM magnesium, the sum of the components was 340 +/- 120% of the control two-component EPSP (p < 0.01; N = 6). These results suggest that in controls, the AMPA and NMDA components of EPSP inhibit each other. The mutual inhibition of components may be an important factor affecting the conductivity and plastic properties of central glutamatergic synaptic pathways.

[Selective suppression of the direct and feedback "fast" inhibition during local administration of picrotoxin in the CA1 region of rat hippocampal slices]. / Selektivnoe podavlenie priamogo i vozvratnogo "bystrogo" tormozheniia pri lokal'noi applikatsii pikrotoksina na CA1 oblast' srezov gippokampa krysy.

Application of picrotoxin to apical dendrites in the CA1 area of the rat hippocampal slices increased the duration of focal potentials (FP) in the stratum radiatum but did not affect the unit activity spikes' amplitude in the stratum pyramidalis, the finding suggesting a suppression of the feed-forward inhibition with no effect upon the recurrent one. The data obtained shows that, under conditions normally used for studying the NMDA-EPSP feed-forward, the inhibition is not invariably suppressed and may affect the results of the studies.

[Synaptic plasticity in the hippocampus during afferent activation reproducing a theta-rhythm pattern (theta plasticity)]. / Sinapticheskaia plastichnost' v gippokampe pri afferentnoi aktivatsii, vosproizvodiashchei pattern teta-ritma (teta-plastichnost').

The data are reviewed concerning synaptic plasticity of the hippocampal monosynaptic pathways evoked by afferent activation which simulates activity of neurons in theta-rhythm. Activation with short high-frequency bursts applied with 5 Hz frequency effectively induces long-term potentiation. In contrast, activation with single pulses at 5 Hz causes the depotentiation or even long-term depression of the activated synapses. "In-phase" activation of two afferent pathways in the theta-rhythm induces long-term potentiation, while the "out-of-phase" activation induces long-term depression of a "weak"" pathway. A train of 30-50 pulses at 5 Hz evokes heterosynaptic short-term depression, i.e., a suppression of all synaptic inputs for 1 min. So-called "hidden" plasticity (the enhancement of the effect of delayed activation in producing long-term depression) is also effectively evoked by the theta-like activatory patterns. Therefore, practically all known types of synaptic plasticity can be effectively evoked by the afferent activation which reproduce the pattern of the hippocampal theta-rhythm. These phenomena can underlie the theta-rhythm participation in learning and memory.

[Reciprocal suppression of the AMPA and NMDA components of the excitatory postsynaptic potentials in the CA1 area of the rat hippocampus in vitro]. / Retsiproknoe podavlenie AMPA- i NMDA-komponentov vozbuzhdaiushchikh postsinapticheskikh potentsialov v oblasti CA1 gippokampa krys in vitro.

The interaction between N-methyl-d-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-dependent components of excitatory postsynaptic potentials (EPSP) was studied in rat hippocampal slices. Responses evoked by stimulation of the collateral commissural fibers were recorded in the radial layer of the CA1 area. Contribution of the NMDA component was changed by application of solutions with different concentrations of magnesium. In solutions with low magnesium concentration, when both AMPA and NMDA components contribute significantly to EPSP, suppression of one of the components by application of selective antagonist resulted in increase in the area of another component. Thus, the sum of pharmacologically isolated AMPA and NMDA components was significantly higher than the control EPSP. For example, at 0.1 mM of magnesium in the extracellular solution the sum of the components was 340 +/- 120% of the control EPSP (p < 0.01, N = 6). The data imply that under the control conditions the EPSP components suppress each other. The mutual suppression of the AMPA and NMDA component of the EPSP can be an important factor which influences the conductivity and plastic properties of central glutamatergic synaptic pathways.

[Long-term potentiation of the NMDA-dependent component of the EPSP in the hippocampus]. / Dlitel'naia potentsiatsiia NMDA-zavisimogo komponenta VPSP v gippokampe.

In the hippocampus, excitatory postsynaptic potential (EPSP) consists of two components, which are related to activation of different types of glutamate receptors. The first component is related to activation of receptors, sensitive to kainate and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and the second one to N-methyl-D-aspartate (NMDA) (AMPA- and NMDA-EPSP respectively). The components are differently changed after induction of long-term potentiation (LTP), which is a known model for cellular mechanisms of learning, memory and a number of pathological processes. Activation of NMDA-receptors is a necessary step of induction of LTP, whereas maintenance of LTP related mainly with increase of AMPA-EPSP. However, in some situations NMDA-EPSP could be also increased after tetanisation or other influences which induce LTP. The increase of NMDA-EPSP could be an important neural mechanism for learning and memory or for neurodegenerative processes, related to disfunction of memory. Recent experimental data and hypothesis about mechanisms of NMDA-EPSP LTP are reviewed.

Atropine inhibits associative potentiation in the hippocampus.

The effects of the muscarinic receptor blocker atropine on associative long-term potentiation were studied in the CA1 region of the rat hippocampus. Focal excitatory post-synaptic potentials (EPSP) were recorded in living slices. Local application of atropine (0.1 mM) significantly inhibited associative long-term potentiation (40-60 min after tetanization) in the "weak" input (str. radiatum 128 +/- 10% compared with 168 +/- 9% in controls). Long-term potentiation at the "strong" input (str. oriens) was increased relative to the control (from 137 +/- 13% to 158 +/- 4%). These results indicate that endogenous acetylcholine aids the development of long-term potentiation in synapses with low levels of activation.

[Atropine suppresses associative potentiation in the hippocampus]. / Atropin podavliaet assotsiativnuiu potentsiatsiiu v gippokampe.

The effect of the muscarinic antagonist atropine on associative long-term potentiation of the CA1 population EPSPs was studied in rat hippocampal slices. Local application of atropine (10(-4) M) significantly suppressed associative long-term potentiation (40-60 min after the tetanization) in a <> input (str. Radiatum 128 +/- 10% vs 168 +/- 9% in control, p < 0.03). Long term potentiation in the <> input itself was not suppressed and even tended to be enhanced by atropine (str. Oriens 158 +/- 4% vs 137 +/- 13 during control). The results suggest that synaptically released endogenous acethylcholine supports induction of long-term potentiation in the synapses with a low level of activation.

[Role of direct and feedback inhibition in the effect of "priming" in hippocampus slices]. / Uchastie priamogo i vozvratnogo tormozheniia v éffekte "praiminga" v srezakh gippokampa.

Field potentials (FP) were recorded from radial and pyramidal layers of the mice hippocampus after conditioning and testing stimulations of the Schaffer collaterals. The effect of a preliminary conditioning stimulus on the tested responses (the "priming" effect) was studied for different testing intensities and interstimulus intervals of 50 to 5000 ms. Two series of experiments were conducted. In the first series the influence of the conditioning stimulus delivered with the interval of 200 ms on the testing stimuli of various intensities was studied. The duration of the testing FP in the radial layer was measured. The plot of the FP duration against the stimulus strength revealed three regions. For the first region (at small stimulus intensities) the FP duration was maximal and independent on the stimulus intensities. The second region began at the point where FP duration reduced presumably due to the feed-forward inhibition. The conditioning stimulus caused a widening (recovery) of the FP due to suppression of the inhibition. In the third region the stimulus intensity was sufficient to excite pyramidal cells and therefore to activate the feed-back inhibition. The time course of the FP was contaminated by the population spike and FP duration became inadequate for the evaluation of the "priming" effect. The second set of the experiments was aimed to study possible changes in the feed-back inhibition. With this end in view the influence of the conditioning (priming) procedure on the paired-pulse depression was studied. The main effect of the conditioning was a suppression of the paired-pulse depression, i.e. a suppression of the feed-back inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

[The effect of picrotoxin and the duration of conditioning on the induction of associative long-term potentiation in field CA1 of the mouse hippocampus in vitro]. / Vliianie pikrotoksina i prodolzhitel'nosti konditsirovaniia na induktsiiu assotsiativnoi dlitel'noi potentsiatsii v oblasti CA1 gippokampa myshei in vitro.

Field potentials were recorded from stratum radiation of CA1 region of mouse hippocampal slices in response to distal Schaffer collateral stimulation (S2). Associative long-term potentiation (ALTP) was induced by simultaneous tetanization of C2 together with proximal Schaffer collateral tetanization (C1). Effects of simultaneous (C1 and C2) and successive (C1 precedes C2 for 200 ms) activation of two inputs were compared. Tetanizations with a foregoing activation of Cl ("conditioning" input) were more effective in experiments with short (30 ms, 100 Hz) trains of pulses. Simultaneous activation of two inputs was more effective when S1 input was tetanized with long (150 ms) trains or synaptic inhibition was blocked by picrotoxin (5.10(-6mM). It is suggested that ALTP induced by short trains of pulses with intervals of 200 ms is a more adequate model of memory than that induced by long-lasting tetanic trains.

[Suppression of the "fast" IPSP when superimposed on the "slow" IPSP as a possible cause of priming in the mouse hippocampus]. / Podavlenie "bystrogo" TPSP pri nalozhenii ego na "medlennyi" TPSP kak vozmozhnaia prichina praiminga v gippokampe myshi.

Extra- and intracellular responses of the mouse hippocampus were recorded at CA1 region after stimulation of two independent inputs from the Schaffer collateral/commissural fibres: conditioning or priming input (C1) and testing or primed one (C2). Duration and amplitude of primed field potentials (FP) and excitatory postsynaptic potentials (EPSP) as well as amplitudes of early (IPSPa) and late (IPSPb) components of inhibitory postsynaptic potentials (IPSP) were measured with variation of C1-C2 intervals from 0 to 1 s. An increase in the FP duration as well as EPSP duration and amplitude and suppression of the IPSP amplitude occurred after conditioning with intervals of 50-500 ms, maximal effect was at 200 ms ("priming" effect). These changes correlated with the amplitude of priming IPSPb. The most prominent effect was observed in cells with hyperpolarizing IPSPa. It is assumed that primed FP and EPSP increase due to suppression of the primed IPSPa, when it is superimposed on the priming IPSPb.

[Disordered associative long-term potentiation in the hippocampus after the tetanization of the reinforcing input]. / Narushenie assotsiativnoi dlitel'noi potentsiatsii v gippokampe posle tetanizatsii podkrepliaiushchego vkhoda.

Field potentials (FPs) were recorded from stratum radiatum of CA1 region of mouse hippocampal slices after weak orthodromic stimulation (C2). Associative long-term potentiation (ALTP), induced by simultaneous tetanization of C2 with strong tetanization of another group of fibres (C1) was investigated. Effects of the additional tetanization of C1 delivered 50-300 ms before and 50-300 ms after conjoint tetanization of two inputs were compared. In experiments with intervals 50-200 ms preliminary tetanizations of C1 suppressed ALTP (the FPs amplitude increase was 10.4 +/- 5.2%) in comparison with procedure in which an additional tetanization of C1 follows conjoint tetanization (the FPs increase was 32.4 +/- 5.3%). There was no significant difference between two procedures in experiments with 300 ms intervals. Three mechanisms have been considered to explain the influence of the preliminary strong tetanus on ALTP: inactivation of "fast" calcium channels, afterburst hyperpolarization and synaptic inhibition. It is suggested that mechanisms of this suppression are similar to mechanisms underlying relative inefficacy of the "backward" association procedure in behavioral conditioning.