Biomedical subjects
Publications and source records attributed to A N Chepkova.
Long-term potentiation of CA1 field potentials was induced by weak tetanic orthodromic stimulation of the Schaffer collateral/commissural fibers in isolated hippocampal slices perfused with a medium containing arginine vasopressin fragment AVP(4-9)in micromolar concentrations. It is hypothesized that AVP(4-9)affects induction of long-term potentiation at the intracellular level.
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Use-dependent alterations in synaptic efficacy are believed to form the basis for such complex brain functions as learning and memory and significantly contribute to the development of neuronal networks. The algorithm of synapse modification proposed by Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols in which postsynaptic cell depolarization through the recording microelectrode was used to reveal the manifestation of Hebb-type plasticity in the synaptic inputs of the neocortex and hippocampus. Special attention is focused on the inhibitory control of the Hebb-type plasticity. Disinhibition within the local neuronal circuits is considered to be an important factor in Hebbian plasticity, contributing to such phenomena as priming, primed burst potentiation, hippocampal theta-rhythm and cortical arousal. The role of various transmitters (acetylcholine, norepinephrine, gamma-amino-butyric acid) in disinhibition is discussed with a special emphasis on the brain noradrenergic system. Possible mechanisms of Hebbian synapse modification and their modulation by memory enhancing substances are considered. It is suggested that along with their involvement in disinhibition processes these substances may control Hebb-type plasticity through intracellular second messenger systems.
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Vasopressin (VP) is axonally distributed in many brain structures, including the ventral hippocampus. Picogram quantities of VP injected into the hippocampus improve the passive avoidance response of rats, presumably by enhancing memory processes. Vasopressin is metabolized by the brain tissue into shorter peptides, such as [pGlu4,Cyt6]VP(4-9) and [pGlu4,Cyt6]VP(4-8), which preserve the behavioral activity but lose the peripheral activities of the parent hormone. Using brain slices, we investigated whether VP or VP(4-8) affects excitatory postsynaptic potentials (EPSPs) and/or membrane responses to depolarization in neurons of the CA1/subiculum of the ventral hippocampus. The EPSPs were evoked by stimulating the striatum radiatum of the CA1 field; the membrane responses were elicited by current injections. Exposure of slices for 15 min to 0.1 nM solution of these peptides resulted in an increase in the amplitude and slope of the EPSPs in 21 neurons (67%) tested. No consistent change in either the resting membrane potential or the input resistance of the neurons was observed. The peptide-induced increase in EPSPs reached a maximum 30-45 min after peptide application. In 14 of these neurons (66%), the peptide-induced increase in EPSPs remained throughout the entire 60-120 min washout period. In the remaining 7 neurons (33%), the initial increase in EPSPs amplitude was followed by a gradual decline to the pre-administration level. The increase in EPSP amplitude was often, but not always, associated with a decrease in the threshold and increase in the number of action potentials in response to depolarizing current injection. Suppression of GABAA receptor-mediated inhibition and N-methyl-D-aspartate (NMDA) receptor-mediated excitation did not prevent the effects of VP and VP(4-8) on the EPSP amplitude or the threshold for action potentials. The results demonstrate that 0.1 nM concentrations of these neuropeptides can elicit a long-lasting enhancement of the excitability of CA1/subiculum neurons of the ventral hippocampus to excitatory, glutamatergic synaptic input. This novel action of VP and its metabolite in the ventral hippocampus may be the physiological action, mediating the memory-enhancing effect of these peptides.
The characteristics of long-term potentiation (LTP) in the hippocampus of rats prenatally exposed to ethanol and treated postnatally with nootropic compounds L-pyroglutamyl-D-alanine-amide (L-pGlu-D-AlaNH2, PGA) or piracetam were studied using in vitro slice preparations. LTP was induced in the CA1 region by the orthodromic stimulation of the stratum radiatum with one train of 100 pulses (100 Hz, 1 s). The probability of LTP development in the hippocampus of young rats was significantly reduced by prenatal exposure to alcohol. This plasticity deficit was completely reversed by daily injections of PGA, 1 mg/kg for 12 days (8-19 days of postnatal development) but not of piracetam, 100 mg/kg. PGA (0.5 microM) also prevented the inhibition of LTP development in hippocampal slices perfused with ethanol, 20 or 50 mM. The data indicate that PGA effectively restores synaptic plasticity after both prenatal and acute exposure to ethanol and suggest that impaired LTP may be a useful model for studying the mechanisms of action of nootropic compounds.
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The tetanic stimulation of the Schaffer collaterals (SC) in rat hippocamp slices after 6 hrs in vitro conditions did not produce long-term potentiation (LTP) of the field response amplitude in the CA1 pyramidal cell layer. In contrast, LTP after the late tetanization was well preserved in the slices that were perfused for 20 minutes with 0.5 mkM L-pGlu-D-Ala-NH2 (PGAA) after 4-4.5 hrs in vitro. There were no significant reactivity changes during the perfusion of the slices with this drug concentration. Two other drugs with nootropic activity, piracetam (100 mkM) and gamma-hydroxybutyrate (100 mkM, Na-salt) did not prevent the disappearance of LTP in the late period in vitro, while enhanced the reactivity during perfusion period. The maintenance of the plastic properties of the SC-CA1 synaptic transmission under the influence of PGAA is thought to be the result of some specific interaction of the drug with LTP induction mechanisms. LTP damaged in the late period in vitro might be a new model of memory disturbances and this model can turn out to be useful for the comparative estimation of the effectiveness of the drugs with proposed nootropic activity and for the analysis of the possible mechanisms of their action.
The effects of amiridin (9-amino-2,3,5,6,7,8-hexahydro-IH-cyclopenta(b) quinoline) and tacrine (1,2,3,4-tetrahydro-9-aminoacridine) on Schaffer collaterals--CAI field potentials were compared in rat hippocampal slice preparations. Similar dose-dependent increase in pop-spike amplitude was observed during slice perfusion with low concentrations of amiridin (5-50 microM) or tacrine (0.5-10 microM). This facilitation was not always fully reversible. The effect was accompanied by slight decrease in pop-EPSP amplitude suggesting membrane depolarization as a possible mechanism of pop-spike facilitation. Further increase in drug concentrations led to the depression and full blockade of pop-spike, that was associated with significant decrease in the pop-EPSP and fiber potential amplitudes. In contrast structurally related 4-aminopyridine evoked dose-dependent increase in both pop-EPSP and pop-spike amplitudes with all the concentrations tested (0.05-1000 microM), this facilitation was transformed into epileptiform response with 4-aminopyridine concentration about 500 microM. Possible mechanisms of drug actions on hippocampal neuron reactivity are discussed. It is suggested that amiridin might turn to be as effective as tacrine in symptomatic treatment of Alzheimer disease.
The effects of kyotorphin (Tyr-Arg) on CA1 and CA3 field responses were studied on rat hippocampal slice preparations. Slice perfusion with 10(-6)-10(-4) M of kyotorphin resulted in reactivity changes both in mossy fibers (CA3) and Schaffer collaterals (CA1). The principal effect was the increase in pop-spike amplitude. Kyotrophin (10(-6)-10(-5) M) and metenkephalin (10(-7)-10(-6) M) were found to produce similar reactivity changes (facilitation) in CA1 region of most preparations. However, kyotorphin effect, in contrast to enkephalin-induced facilitation was not blocked by naloxone. The data suggest that the mechanisms of kyotorphin action in the hippocamp are not related to endogenous enkephalin release.
Intracerebroventricular administration of 166 nmoles of the exogenic opioid beta-casomorphin (5) produced a potent and reversible depression of the compound action potential evoked in dentate granule cells by stimulation of the medial perforant path, whereas the extracellularly recorded excitatory postsynaptic potential is left unchanged. This in vivo effect of beta-casomorphin was obviously different from those observed previously in the CA 1 region in hippocampal slice experiments. The results suggest that more than one opioid mechanism determines the granule cell excitability. Some of the possible mechanisms involved in the effects of beta-casomorphins in the hippocampus are briefly discussed.
Long-term potentiation (LTP) was induced in the dentate gyrus of freely moving rats by tetanic stimulation of the medial entorhinal cortex under conditions of catecholamine depletion by 200 mg/kg alpha-Methyl-para-tyrosine (AMPT) or blockade of alleged dopamine receptors by 0.5 mg/kg haloperidol. Both substances did not change significantly the normal excitability of the glutamatergic perforant pathway, but affected the establishment of LTP. Whereas the potentiation effect on the EPSP component of the monosynaptic field potential was not changed by both substances when compared to the potentiation of controls, the potentiation of the population spike was prolonged and enhanced. These results point to an effect of catecholaminergic blockade on postsynaptic membranes of the target cells or on other components of the neuronal network but not to a specific influence on the homosynaptic mechanisms of LTP.
The effects of leu- and metenkephalin administration into the perfusion medium on CA-1 and CA-3 pyramidal cell reactivity to electric stimulation of Shaffer collaterals and mossy fibers, respectively, were investigated on mice hippocampal slice preparations. The reactivity changes were measured by amplitude changes in focal potential, which reflected a synchronous pyramidal cell discharge (population spike, PS). Infusion of 10(-6) M leu- or metenkephalin resulted in a rapid and reversible 200-300% increase in the PS amplitude in CA-1 field of the hippocamp, that was blocked by preliminary administration of 10(-5) M naloxone. An increase in the PS amplitude in CA-3 region was observed as a result of the infusion of much higher enkephalin concentrations (10(-4) M) and did not exceed 50%. The data obtained allow the conclusion that enkephalins enhance the reactivity in the two main intrahippocampal synaptic systems but have a more pronounced effect on CA-1 pyramids.
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Light flashes and single electrical stimuli applied to the nucleus ventro-posterolateralis and to the LGB evoked protracted IPSPs in visual and sensorimotor cortical neurons respectively. High-frequency stimulation of the midbrain RF suppressed these IPSPs which was manifested in a shortening of the inhibitory pause and in a decrease in the amplitude of the IPSPs up to their complete elimination (disinhibition). Activation of noradrenergic pathways by stimuli applied to the locus coeruleus or to the lateral hypothalamus led to the same result. The suppression of cortical IPSPs followed by facilitation of cortical unit firing in response to thalamic or peripheral stimulation seems to be an imprortant mechanism underlying arousal.
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The effects of infusion of low concentrations of the synthetic opioid peptide D-Pro4-beta-casomorphin-5(deprolorphin) on electrical field responses in the in vitro hippocampal slice preparation of mice were investigated. Deprolorphin (0.01-10 microM) causes a large enhancement of the population spike (PS) and appearance of additional spikes of CA1 pyramidal cells to Schaffer-commissural stimulation, which were partially antagonized by the opiate receptor antagonist naloxone. It is likely that this analgesic peptide in the hippocampus acts through mu-receptors and neuronal mechanisms already described for morphine and enkephalin analogs.
Pavlovian conditioning has been considered as one of the principal experimental approaches to understanding such complex brain functions as learning and memory. Use-dependent alterations in synaptic efficacy are believed to form the basis for these functions. The algorithm of synapse modification proposed by D. Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols which were used to reveal the manifestations of Hebb-type plasticity in the synaptic inputs to neocortical and hippocampal neurons. Special attention is focused on long-term modifications of synaptic efficacy in the hippocampus as a possible neuronal mechanism of learning and the role of disinhibition in their development. The effects of various neuromodulators on hippocampal long-term potentiation are considered. It is suggested that along with their involvement in disinhibition processes these substances may control the Hebb-type plasticity through intracellular second messenger systems.