A. N. Chepkova

Hebbian synapses in cortical and hippocampal pathways.

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.

Nootropic compound l-pyroglutamyl-d-alanine-amide restores hippocampal long-term potentiation impaired by exposure to ethanol in rats

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.

Arginine Vasopressin Fragment AVP 4-9 Facilitates Induction of Long-Term Potentiation in the Hippocampus

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 AVP4-9 in micromolar concentrations. It is hypothesized that AVP4-9 affects induction of long-term potentiation at the intracellular level.

Effects of deprolorphin, a casomorphin analog, on hippocampal CA1 field potentials in vitro.

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.

Impaired plasticity of hippocampal synaptic transmission in rats exposed to prenatal hypoxia is normalized by treatment with nootropic dipeptides

Experiments on hippocampal slices from young rats exposed to hypobaric hypoxia duringin utero development revealed enhanced responsiveness (an increase in a CA1 field response amplitude) and reduced plasticity (a low incidence of field response long-term potentation following high-frequency stimulation) of CA1 pyramidal neurons. Postnatal treatment of animals with piracetam peptide analogs constructed on the basis of pyroglutamate and proline normalized both these physiological indices.

Pyroglutamyl-Asparagine Amide Normalizes Long-Term Potentiation in Rat Hippocampal Slices

Preapplication of peptide piracetam analogue pyroglutamyl-asparagine amide to rat hippocampal slices facilitates long-term potentiation of focal responses in the CA1 field after weak tetanization of the synaptic input (30 pulses, 100 Hz). This treatment normalized the development of long-term potentiation after standard tetanization (100 pulses, 100 Hz) impaired by ethanol.

Effect of Pyroglutamylasparagine Amide on Plastic Characteristics of Synaptic Transmission in the Hippocampus

Preincubation of rat hippocampal slices with 0.05-0.5 μM pyroglutamylasparagine amide improved characteristics of long-term potentiation of focal responses in the synaptic system of Schaffer collaterals-CA1 field pyramids facilitating LTP development and increasing its amplitude and duration. Presumably, the positive modulation of plastic characteristics of synaptic transmission in the hippocampusis is responsible for facilitation of learning and memory induced by pyroglutamylasparagine.

Thyrotropin-releasing hormone inhibits long-term potentiation in synaptic systems of rat hippocampus

The effects of thyrotropin-releasing hormone (TRH) on long-term potentiation of field responses in mossy fibers—CA3 and Shaffer collaterals—CA1 synaptic systems were studied on rat hippocampal slices. Incubation with micromolar concentrations of TRH inhibited the development of long-term potentiation in both synaptic systems. It is suggested that this phenomenon underlies the antiamnesic effect of TRH.

Piracetam peptide analog L-PGLU-D-Ala-NH2 maintains the plastic properties of synaptic transmission in long-lasting hippocampal slices

Short-term high-frequency stimulation of afferent hippocampal inputs leads to increased reactivity of postsynaptic neurons, which may last many hours. This plastic phenomenon, known as long-term potentiation (LTP), is nowadays regarded as the neurophysiological basis of learning and memory [6, 9]. The mechanism of development and preservation of LTP have been studied most intensively on surviving hippocampal slices in the system of Schaffers collaterals, connecting the two output systems of the hippocampus, namely the pyramids of areas CA3 and CA1 [6]. Several investigations have been conducted on this same synaptic system in order to study the action of substances affecting learning and memory on LTP [9]. The first attempts to evaluate the action of nootropic drugs agents selectively improving memory and cognitive functions on LTP gave negative results: the characteristics of LTP in the system of Schaffers collaterals area CA1 pyramids in hippocampal slices were unchanged after application of various does of the standard preparation (piracetam) and of a substance of different chemical nature (bifemelane) [7, 8]. However, nootropic drugs are known to be effective in the case of memory disturbances due to various causes, but have virtually no effect on normal memory. In a search for a more adequate model of damaged LTP, we directed our attention to the fact that LTP develops easily in hippocampal slices and persists for a long time during high-frequency stimulation (tetanization) of the input in about the first 4 h after preparation of the specimen and it rarely appears after tetanization in the later stages, although all other electrophysiological characteristics, including shortterm plastic phenomena (frequency and post-tetanic potentiation) remain intact. The aim of the present investigation was to assess the effect of nootropic drugs on the development of LTP in long-surviving hippocampal slices, subjected to tetanization in the late periods. Another aim of the investigation was to compare the action of piracetam and its peptide derivative pyroglutamyl-D-alanine (PGAA), which possesses higher activity and its effective at all stages of learning, as shown by behavioral tests [4].