Long-term potentiation in the hippocampal CA3 to CA1 synapses may be induced in vivo by activation of septal cholinergic inputs.

PURPOSE/AIM: The role of cholinergic neurotransmission in the hippocampus remains controversial since different studies showed either no influence or its modulatory effect on glutamatergic hippocampal synapses. It remains unclear whether septal cholinergic input can modulate plasticity of synapses formed by CA3 pyramids on CA1 neurons. The aim of the study was to clarify the role of septal input in the development of LTP in this synapse. MATERIALS AND METHODS: We recorded in vivo in rats under urethane anesthesia focal excitatory postsynaptic potential (fEPSP) characteristics in CA1 area after stimulation of the ventral hippocampal commissure (VHC), which contains both CA3 axons innervating CA1 neurons and cholinergic axons coming from the medial septum. We performed two series of experiments in which LTP was induced by tetanization of either VHC or medial septal area (MSA). Degeneration of cholinergic neurons in MSA was induced by intraseptal injection of 192IgG-saporin. RESULTS: In both experimental series, tetanization induced an increase in fEPSP amplitude which lasted for at least 40 min after tetanic stimulation, although tetanization of VHC induced a larger increase in fEPSP amplitude compared to MSA tetanization. Elimination of septal cholinergic neurons by 192IgG-saporin abolished LTP development in both experimental series. This suppression of LTP in animals with cholinergic deficit was not due to loss of hippocampal neurons. CONCLUSIONS: Our data suggest that activation of septal cholinergic fibers during tetanization is a critical factor of LTP induction in the hippocampal CA3 to CA1 synapses.

[Propranolol Impairs Memory Reconsolidation at Single and Multiple Paired with Tone Painful Electrocutaneous Stimulations].

In the current paper there were used two methods for assessment of the propranolol effect on reactivated memory at reconsolidation phase--a classical pavlovian conditioning and the two-ways escape reflex. The difference between these two models was that in the first case a tone was paired with electrocutaneous painful stimulation only once, while in the second case it was applied multiply. Reminding was produced in the first case by placing the animals into the same context, whereas in the second case by application of the same amount of pairings of conditional and unconditional stimuli as it was used at the first day of learning. Propranolol reduced intensity of freezing reaction on 25% from the baseline at the classical conditioning approach and practically led to disappearance of memory and complete regress of the two-ways escape reflex. There was suggested on existence of the possible different mechanisms of noradrenergic blockade on memory loss at the stage of its reconsolidation in the used models of learning.

[A Role of the Wnt Signaling in the Regulation of Brain Function].

The review describes the Writ signaling pathway participation in the embryonic development, such as cell specification, migration and polarity. Recent studies have shown that the Wnt pathway plays one of the key roles in the processes of synaptic plasticity and memory formation. In this review there are evidences of the Wnt cascade involvement in the modulation of synaptic efficacy at both pre- and postsynaptic levels. Here we analyze the role of Wnt ligands in synaptic plasticity and behavior. Finally, we describe that components of Wnt pathways are involved in the development of major neurological and psychiatric disorders, including a neuroprotective role of Wnt proteins in the pathogenesis of Alzheimer's disease.

NGF but not BDNF overexpression protects hippocampal LTP from beta-amyloid-induced impairment.

Two major neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are involved in a number of physiological processes associated with neuronal growth, survival and plasticity. There are an increasing number of papers demonstrating their ability to serve as neuroprotective molecules under various pathological conditions. At the same time, it remains unclear whether both NGF and BDNF have similar roles under pathological conditions and their effects on the electrophysiological properties of neurons after acute pathogen exposure. In the present paper we investigated the neuroprotective role of these two neurotrophins in a well-characterized model of beta-amyloid peptide (Aß)-dependent impairment of long-term potentiation (LTP). Using lentiviral gene delivery we performed long-term elevation of neurotrophin expression in the dentate gyrus (DG) of rats. One week after virus injection acute brain slices were incubated with beta-amyloid (25-35) for 1h and afterward in vitro LTP induction was performed in medial perforant path-DG synapses. We demonstrate that chronic elevation of NGF but not BDNF concentration protects LTP induction from beta-amyloid action. Further inhibitory analysis suggests that the effect of NGF is mediated by PI3K-signaling cascade.

Administration of nicotinic receptor antagonists during the period of memory consolidation affects passive avoidance learning and modulates synaptic efficiency in the CA1 region in vivo.

We examined whether a non-selective antagonist of nAChRs mecamylamine and selective antagonists of α4ß2-containing nAChRs dihydro-ß-erythroidine (DHßE) and α7-containing nAChRs methyllycaconitine (MLA) affect learning performance and synaptic efficiency in the CA1 area of the hippocampus of freely moving rats during the memory consolidation period. Adult male Wistar rats received mecamylamine (0.5 mg/kg), DHßE (1 mg/kg), MLA (2 mg/kg) or saline immediately after training in a passive avoidance task. Memory retention was examined 24 h after the training. The changes in the latency of the first entry into a dark compartment of a test chamber were chosen as a criterion of learning. The ability of nAChRs antagonists to induce changes in the basal level of focal potentials (fEPSP, field excitatory postsynaptic potential) was estimated before training (baseline), 90 min after the training (consolidation period) and 24 h after the training (retention period). We found that in untrained rats mecamylamine, DHßE and MLA diminished the amplitude of fEPSP within the first 90 min after the injection; similar effect was observed in DHßE- and MLA-treated trained animals. These suppressive effects of DHßE and MLA were associated with memory loss. In contrast, mecamylamine, when applied to trained animals, tended to increase latency to enter the dark chamber and did not influence fEPSP during first 90 min after injection. Thus, the nAChRs antagonists with different selectivity induced different changes in fEPSP and behavior which suggests that nAChRs with different subunit composition are diversely involved in memory consolidation.

[The key role of calcium in the mechanism of deprivational potentiation of population responses in hippocampal CA1 neurons].

We investigated a role of calcium in the mechanisms of deprivational potentiation (DeP) of the popspikes amplitude of CA1 neurons that was induced in consequence of long (60 min) interruption of rare test stimulation (0.05 Hz) of Schaffer collaterals in rat hippocampal slices. There are two phases of deprivational potentiation that have presumably different genesis: short-term initial "peak" (about 12 min) and long-term "plateau" (more than 1 h). The presence of the membrane permeable Ca2+ chelator (BAPTA-AM) in the solution, or decrease of [Ca2+](out), or depletion of intracellular Ca2+ stores (in the presence of thapsigargin/cyclopiazonic acid) led to reduction of the short-term and to suppression of the long-term phases of DeP. Thus the key role of calcium in the DeP induction mechanisms and participation of two main sources (the extracellular environment and the intracellular Ca2+ stores) was demonstrated.

[Consolidation, reactivation and reconsolidation of memory].

In this review the data on consolidation and reconsolidation of memory by its reactivation (reminding) by a conditional stimulus or context are presented. A special attention is paid to "time windows" when amnesic and other interventions during memory reconsolidation become effective. The similarities and differences between consolidation of original learning and repeated consolidation (reconsolidation) during reactivation of memory by a conditional stimulus or context are considered. The hypotheses about memory updating during reconsolidation and some possible ways affecting memory are also discussed.

[Restoration of long-term potentiation by food delivery to deprived rat].

The possibility of restoration of the extinguished long-term potentiation at the Shafer collaterals projections in food deprived rats to small amounts of meal was studied. Giving a small portion of meal restores a population spike's amplitude for the first CA1 response to paired-pulse stimulation. The amplitude of the population spike for the second response restored completely. Giving a small portion of meal in control groups of deprived animals without preliminary acquisition of potentiation did not produce changes of the CA1 evoked responses. Restoration of potentiation in the described experiments is likely to be related with a certain level of animal's emotional tension. It is assumed that a restoration of potentiation at natural conditions could be necessary for solution of tasks related with satisfaction of biologically important for animal needs.

[Involvement of Wnt signaling in hippocampal plasticity].

Wnt signaling is a signal transduction pathway involving peptides of Wnt family as key molecules. In this review, the data on the role of canonical and non-canonical Wnt pathway in hippocampal structural and synaptic plasticity have been analyzed. Wnt-mediated signal transduction is involved in normal functional plasticity, and the disturbances in Wnt-mediated mechanisms form a basis for the development of cerebral pathologies. A special attention is devoted to glycogen synthase kinase 3beta (GSK-3beta), one of most important from both plasticity and pathology perspectives component of the canonical Wnt pathway. The studies in this area, besides their fundamental significance, are important for translation to the medicine, and the key components of the Wnt pathway are potential targets for the developmentn of pathogenetical therapeutics for a number of socially significant cerebral pathologies.

[Influence of CA1 hippocampal field on theta-activity in rats under urethane anesthesia].

The influence of CA1 hippocampal field on the theta-activity production depending on the efficiency of CA1 synaptic inputs was studied in urethanized rats. The long-term posttetanic potentiation (LTP) of Shaffer collaterals resulted in an increase in the theta-power in hippocampal EEG without change in its frequency. A high correlation was shown between the increase in the theta-power and the amplitude of the local potentials induced by LTP. The mechanisms and the functional role of the observed relations between the LTP and theta activity are discussed.

[Study of extracellular concentration of dopamine and its metabolites in mice striatum by a microdialysis technique at intraperitoneal administration of MPTP].

In this paper a structure of a microdialytic cannula inserted into brain areas just before a microdialysis is described. The cannula used allowed to find out a correspondence of behavioral and biochemical changes in C57BL/6 mice at various time intervals after a single dose administration (20 mg/kg) of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, without any additional pharmacological actions enhancing an extracellular striatal dopamine concentration. Immediately after 1-methyl-4-phenyl-1.2,3.6-tetrahydropyridine administration an essential disturbance of mice behavior and a significant reduction of the extracellular concentration of dopamine and homovanillic acid were observed in striatum. A week after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration neither behavior nor the extracellular dopamine and homovanillic acid striatal concentration substantially differed from those of controls. 30 days after the neurotoxin administration there was again an essential disturbance of behavior and the large reduction of dopamine and its metabolite concentration in striatum. There was suggested that a reduction of the dopamine concentration immediately after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection connected with abnormalities of dopamine synthesis and metabolism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine whereas a reduction of the extracellular striatal dopamine concentration 30 days after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration related to damage of the nigrastriatal dopaminergic system.

[A long-term posttetanic potentiation of hippocampal evoked potentials under conditions of enriched environment].

The influence of enriched environment on the long-term posttetanic potentiation of hippocampal evoked potentials is discussed. The attention is focused on the effects of novelty, aging and the influence of enriched environment on synaptic processes in hippocampal neurons in transgenic animals. The evidence that the exposure to the enrichment of the environments prevents the negative effects of stress and other unfavorable factors on the long-term posttetanic potentiation, learning and memory is presented. The molecular-biochemical, neurochemical, neurophysiological and morphological mechanisms underling synaptic changes responsible for the transformation of hippocampal long-term potentiation under exposure to the enriched environment are considered.

Conditions required for the appearance of double responses in hippocampal field CA1 to application of single stimuli to Shäffer collaterals in freely moving rats.

Stimulation of Shäffer collaterals with single current impulses could evoke double responses in hippocampal field CA1 in freely moving rats. The late response - the population excitatory postsynaptic potential with a preceding transient potential, often biphasic - occurred only after an early population spike and was time-locked to it. The shape characteristics of the late response, its polarity, and its latent period relative to the early population spike suggest that stimulation of Shäffer collaterals gives rise, in CA1, to a wave of excitation which passes through the entorhinal cortex and returns to CA1 directly via fibers of the perforant path. In conscious rats, medium-strength stimulation of Shäffer collaterals, sufficient to evoke a quite early population spike in CA1, did not usually lead to the appearance of a late response; the same stimulation became effective after tetanization of Shäffer collaterals in conditions of long-term potentiation of the early population spike. Furthermore, the appearance of the late response was facilitated in rats falling asleep on the background of high-amplitude, low-frequency EEG oscillations in CA1 characteristic of slow-wave sleep, as well as in sleeping rats, regardless of the EEG pattern.

[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.

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses.

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg/kg) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurons and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses.

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg x kg(-1)) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurones and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.

Biphasic effects of atropine on sensory-evoked hippocampal rhythmical slow activity in urethane-anaesthetized rats.

This study investigated the response of hippocampal RSA, recorded from electrodes in CA1 and the contralateral dentate gyrus of urethane-anaesthetized rats, to atropine sulphate administered at 15 min intervals in a cumulative dose-response schedule (1, 3, 10, 50 and 50 mg x kg(-1) i.p.). The power of CA1 and dentate gyrus RSA in the 3-7 Hz band was increased after administering the first 3 doses of atropine (1, 3 and 10 mg x kg(-1) cumulatively) in rats held in the stereotaxic frame or removed from the frame and given electrical sensory stimulation to the base of the tail. This increase in RSA was dependent on sensory input, since it was not seen in animals outside the frame unless sensory stimulation was given, and it was abolished by increasing the dose of atropine (an additional 50 and 50 mg x kg(-1) cumulatively). Methylatropine (6 mg x kg(-1) i.p.) did not increase RSA power. The biphasic effect of atropine on sensory-evoked hippocampal RSA activity may be explained by differential effects at pre- and post-synaptic sites e.g. in the septo-hippocampal system or on pathways processing sensory information.

Studies of the synaptic plasticity of field CA3 of the hippocampus during tetanization of the perforant path.

Studies on living slices of hippocampus-entorhinal cortex formation from adult rats were performed to investigate changes in responses in field CA3 to stimulation of mossy fibers in conditions of perforant path tetanization with different parameters. Tetanization of the perforant path at frequencies of 10 and 100 Hz induced depression of responses in CA3 on testing of this same path. Tetanization of the perforant path at a frequency of 10 Hz and an amplitude subthreshold for potentiating mossy fiber synapses in CA3 became threshold if preceded by tetanization of the perforant path at a frequency of 100 Hz. Tetanization of mossy fibers at 10 Hz resulted in potentiation of the input to CA3, while tetanization at 100 Hz induced depression. High-frequency tetanization of the perforant path (100 Hz) delivered in trains following at the frequency of the theta rhythm, led mainly to depression of field CA3 responses to stimulation of mossy fibers.

[Study of synaptic plasticity of hippocampal CA3 area as a result of tetanization of perforant path]. / Issledovanie sinapticheskoi plastichnosti oblasti CA3 gippokampa pri tetanizatsii perforantnogo puti.

Evoked responses in CA3 area to the mossy fibers stimulation were studied after low and high frequency tetanizations of the perforant path. Stimulations of perforant path with 10 and 100 Hz frequencies inducted depression testing through the same path. Subthreshold for potentiation of the mossy fibers inputs to the CA3 tetanization of the perforant path with 10 Hz frequency transformed to threshold one after previous tetanization of the perforant path with 100 Hz frequency. Tetanization of the mossy inputs to the CA3 with 10 Hz frequency leaded to potentiation whereas tetanization with frequency 100 Hz depressed the same inputs. High frequency tetanizations (100 Hz) of the perforant path with theta-rithm frequency stimulation basically depressed of the CA3 evoked responces to the mossy fiber stimulation.

[Double evoked responses to the electrical stimulation of Shaffer's collaterals in CA1 hippocampal field]. / Dvoinye vyzvannye otvety v pole CA1 gippokampa pri stimuliatsii kollateralei Shaffera.

Double evoked responses to single current pulses applied to Shaffer's collaterals were observed in CAI hippocampal field in freely moving rats. The second response was an irregular population EPSP with constant latency sometimes accompanied by a population spike. The effect was observed in 22 of 54 tested rats (40.74%). In 10 of these 22 animals (45.45%) the second response was evoked by a weak testing stimulus of at least of a single collateral, in the remaining 12 rats the second response appeared to stimulation with increased current or after potentiation of the stimulated pathways. The second responses were very sensitive to the functional state of an animal and were recorded at the state of rest or during sleep. The latencies of the second response measured from the beginning of the first response were very close in different animals and with low intraindividual variability indicating that the same circuits are involved in its generation. It is suggested that hippocampus can support dynamic processes such as reverberation of signals.