[Influence of lateral diffusion on depression of neural cholinsensitivity].

Using mathematical model a comparative analysis of the influence of receptor lateral diffusion, endocytosis and exocytosis of receptors on the change in the number of membrane receptors at rhythmical local applications of a mediator on neural soma was performed. The results allow us to estimate quantitatively the effect of these processes on the length of the period between mediator applications. The necessity of considering the change in the rate of receptor lateral diffusion, while studying the effect of some protein kinases and protein phosphatases on the change in the number of receptors, became evident. The model also provided the effect of "after stimulus efficiency".

[Role of serine/threonine and tyrosine protein phosphatases in command Helix lucorum neurons at the cellular correlate of habituation].

Effects of some inhibitors of serine/threonine and tyrosine protein phosphatases on the depression and spontaneous recovery of the acetylcholine-induced inward current (ACh-current) in command Helix neurons of defensive behavior at the cellular correlate of habituation were investigated. The following drugs were used: okadaic acid (reduces activity ofphosphatases PP1 and PP2A), endothall (PP2A), cyclosporine A and cypermethrin (PP2B), CCT007093 (PPM1D), dephostatin (blocks tyrosine phosphatases). All used inhibitors modify the depression flow, and endothall reduces spontaneous recovery of ACh-current also. Obtained results indicate that changes in cholinosensitivity of command neurons depend on activity of all investigated protein phosphatases. Mathematical model considers the possibility of different localizations of receptors in a neuron and regularity of transitions between them. This model makes it possible to conclude participation indicated phosphatases in mobility of membrane cholinoreceptors ensuring the ACh-current modification at the cellular correlate of habituations. Comparison of experimental and calculated curves of ACh-current change allows to conclude that the main target of protein phosphatases is the transport system of a neuron--cytoskeleton and motor proteins.

[Role of myosins in depression of sensitivity of Helix neurons to acetylcholine in a cellular analog of habituation].

We investigated the involvement of cytoskeleton motor proteins, myosins, in the molecular mechanism of sensitivity depression to acetylcholine in Helix command neurons of defensive behavior in a cellular analog of habituation. There were analyzed the effects of several drugs disturbing myosin function: ML-7 and MLCK-IP-18--blockers of myosin light chain kinase, blebbistatin--an inhibitor of non-muscle myosin II, Y-27632--inhibitor of kinases ROCK-I and ROCK-II (activate mainly non-muscle myosin II) on the depression of acetylcholine-induced inward current. It was found that ML-7 and MLCK-IP- 18 weakened current depression; blebbistatin and Y-27632 did not change the depression. The results of experimental inhibitory analysis and mathematical modeling of the effects of inhibitors on the number of membrane-bound cholinergic receptors allow to suggest the involvement ofmyosins (excluding non-muscle myosin II) in the transports of acetylcholine receptors (endo- and exocytosis) that are responsible for sensitivity changes in neuron somatic membrane to acetylcholine in a cellular analog of habituation.

Cholinergic receptor exocytosis under conditions of depression of acetylcholine-induced current in edible snail neurons in cellular analogue of habituation.

Exocytosis inhibitor Exo 1 potentiates depression of acetylcholine-induced inward current in defensive behavior command neurons of edible snail, when acetylcholine is applied rhythmically to the soma in cellular correlate of habituation. A mathematical model presupposing different receptor localization in the cell and regularities of their translocations made it possible to analyze the dependence of acetylcholine-induced current depression on a number of intracellular processes. It was concluded that depression of choline-sensitive extrasynaptic zones on the membrane of defensive behavior command neurons in edible snail in cellular correlate of habituation is partially determined by attenuation of exocytosis of internalized cholinergic receptors.

[Role of actin microfilaments in depression of acetylcholine-induced current in Helix lucorum neurons on cellular analogue of habituation].

Toxins that impair the function of actin microfilaments in cytoskeleton, cytochalasin B (disrupts microfilaments by inhibiting actin polymerization) and phalloidin (binds polymeric F-actin, stabilizing it and interfering with the function of actin-rich structures) reduce the depression of acetylcholine-induced inward current in Helix lucorum command neurons of defensive behavior during rhythmical local acetylcholine applications to soma (cellular analogue of habituation). These results and mathematical simulation allow us to suggest that the depression of cholinosensitivity of extrasynaptic membrane zones in command neurons on the cellular analogue of habituation is associated with the involvement of actin microfilaments in reduction of the number of membrane cholinoreceptors.

[The role of serine/threonine and tyrosine protein kinases in the depression of cholinosensitivity in Helix lucorum neurons in the cellular correlate of habituation].

Inhibitor ofadenylate cyclase (SQ 22,536) and inhibitors ofserin/threonine protein kinases A (PKA -Rp-cAMPS), G (PKG - H-Arg-Lys-Arg-Ala-Arg-Lys-Glu-OH), calcium/calmodulin-dependent kinase II (CaMKII - KN-93), p38mitogen-activated (MAPK - PD 169316), and tyrosine protein kinases (genistein), including their Src-family (PP2), weaken the depression of the acetylcholine-induced inward current (ACh-current) in command Helix neurons of defensive behavior under conditions of rhythmical local acetylcholine applications to the soma in the cellular analogue of habituation. Selective inhibitor of protein kinase C (PKC - chelerythrine) does not change the depression of the ACh-current. Mathematical simulation of the influence of the inhibitors applied on a number of membrane-connected acetylcholine receptors made it possible to obtain the design curves consistent with the experimental curves of the ACh-current depression. The experimental data and the results of calculations allowed us to make the following assumptions. The reversible depression of sensitivity to ACh of command Helix neurons of defensive behavior in the cellular correlate of habituation depends on the decrease in the number of membrane-connected ACh receptors as a result of activation of several serine/threonine protein kinases: A, G, CaMKII, p38 MAPK (without the participation of PKC), and tyrosine protein kinases including the family of Src-kinases. The main targets of all protein kinases under study (excluding PKC) in command neurons are the proteins of cytoskeleton (actin microfilaments and microtubules). Phosphorylation of these proteins evokes polymerization and stabilization ofactin microfilaments, stabilization of the main microtubule protein tubulin, a change in the activity of motor proteins responsible for the speed of receptor endocytosis and exocytosis. The PKG action is indirect via the modification of actin-myosin interaction. Protein kinase A, CaMKII, and tyrosine Src-kinase phosphorylate also proteins activating receptor translocation into clathrin-coated membrane invaginations during endocytosis.

[The possible mechanisms of acetylcholine receptor desensitization].

The postsynaptic mechanisms initiating the development of two acetylcholine receptor states (I and D) which determine the desensitization are discussed. Attention is focused on the processes of receptor endocytosis as the major mechanism of desensitization. General processes and differences in the development of the D state during the desensitization and long-term depression are analyzed. A mathematical model taking into account the membrane and intracellular receptor states is used. This model makes it possible to analyze the influence of some intracellular substances on the receptor internalization and recycling.

[Endocytosis of cholinoreceptors in the mechanism of depression of cholinosensitivity in Helix lucorum neurons in a cellular model of habituation].

Inhibitors of dynamin-dependent endocytosis (dynamin inhibitory peptide and dynasore) and inhibitors of tubulin (colchicine and vinblastine) decrease the depression of acetylcholine-induced inward current in command neurons of Helix defensive behavior under conditions of rhythmical local applications of acetylcholine to a neuron soma in a cellular model of habituation. Mathematical model which allows for the possibility of different localizations of receptors in a neuron and characteristics of receptor travel makes it possible to analyze the dependence of the current depression on some intracellular processes. We suggest that the cholinosensitivity depression of extrasynaptic membrane zones in command neurons of Helix defensive behavior in the cellular model of habituation under study is associated with dynamin-dependent endocytosis of cholinoreceptors with involvement of cytoskeleton microtubules.

[The role of cluster receptor state in synaptic plasticity].

Common postsynaptic mechanisms underlying formation and increase in efficiency of glutamate and GABA synapses are discussed. Much attention is given to clusterization of different receptor types as a mechanism of long-term potentiation. A possibility of synchronization of activities of receptors forming the same cluster is discussed.

[Model of the interreceptor cluster interaction as the basis for increased neuron sensitivity to a mediator].

Inter receptor relations may result in activation of the majority of cluster receptors, when the mediatory concentration is small then to activate "unclucter" receptors. The neuron activation by the small mediatory concentration, the postsynaptic membrane changes under synaptic modification, the one receptor activation by unconnected with him receptor can be explain as results of the cluster receptor influence.

[The role of different conformational states of receptors in the formation of synaptic plasticity].

A mathematical model was proposed that explains the formation of successive temporal stages of synaptic plasticity in terms of the transition of post-synaptic ionotropic receptors to different conformational states.

[Study of giant depolarizing activity in the neonatal hippocampal neurones]. / Issledovanie mekhanizma vozniknoveniya gigantskikh depoliariziruiushchikh potentsialov v neironakh gippokampa novorozhdennykh krys.

Spontaneous oscillatory activity is a general feature of developing neural networks. Early in postnatal development, spontaneous network-driven events, termed giant depolarizing potentials (GDPs), occur synchronously over the entire hippocampus. By performing simulation of hippocampal network with using physiology parameters of the neurons and its network from the present experiments and literature dates, we investigated the participation of the different components of network in the generation of GDPs. Comparing the results of the model and in vitro experiments we conclude that are necessary for the GDP generation involvement the activation of GABAergic, glutamatergic inputs and perhaps gap junction.

Mathematical simulation of the induction of long-term depression in cerebellar Purkinje cells.

The question of the mechanisms underlying the induction of associative and homosynaptic long-term depression in cerebellar Purkinje cells is addressed. Mathematical simulation was used to investigate the possibility that long-term depression, which is associated with a decrease in the efficiency of AMPA receptors, could be induced both by phosphorylation and dephosphorylation of these receptors.

[Modeling features of induction of long term potentiation in pyramidal neurons in the CA3 hippocampal region]. / Modelirovanie osobennostei vyrabotki dlitel'noi potentsiatsii v piramidnom neirone oblasti CA3 gippokampa.

The conditions for inducing the long-term potentiation in the hippocampus were analyzed using the mathematical model of a CA3 pyramidal cell. Their dependence on the physiological characteristics of the neuron, the basic biochemical processes, and inhibitory efficacy was considered. The role of additional membrane depolarization in the origination of the hysteresis of the number of phosphorylated receptors as the basis for the formation of an "intermediate" stage of long-term potentiation was studied.

[Mathematical simulation of induction of long-term depression in cerebellar Purkinje cells]. / Issledovanie mozniknoveniia dlitel'noi depressii v kletkakh Purkin'e mozzhechka s pomoshch'iu matematicheskoi modeli.

Mechanisms of associative and homosynaptic long-term depression (LTD) in cerebellar Purkinje cells are discussed. The possibility of LTD induction related to a decrease in efficacy of AMPA receptors through either their dephosphorylation or phosphorylation is investigated by mathematical simulation.

[Hysteresis of synaptic effectiveness--one of the possible mechanisms for associative learning?]. / Gisterezis sinapticheskoi éffektivnosti--odin iz vozmozhnykh mekhanizmov assotsiativnogo obucheniia.

The conditions on the occurrence of hysteresis of the amount of phosphorylated receptors were determined depending on the rhythmic frequency of presynaptic neuronal activity using the full and simplified models of synaptic plasticity for pyramidal hippocampal neurones. It is assumed that this phenomenon lies at the basis of the conservation of long-term potentiation.

[Mathematical description of modifying synapses of hippocampal pyramidal neurons]. / Matematicheskoe opisanie modifitsiruiushchikhsia sinapsov piramidnykh neironov gippokampa.

The system of differential equations describing the plasticity of the hippocampal pyramidal neuron CA3, developed before, was analyzed. The system was divided into two groups according to magnitudes of the biochemical reaction constants. The first group with large values of the constants was transformed into quasi stationary algebraic equations. This allowed one to transform the system of 32 differential equations to a system containing only 4 differential equations, which can be used for modeling of learning processes in various parts of the brain.

[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.

Studies of long-term potentiation and depression of inhibitory transmission by mathematical modeling of post-synaptic processes.

A mathematical model of posttetanic processes launched by rhythmic stimulation of the excitatory and inhibitory inputs to the dendritic spine of a pyramidal neuron in hippocampal field CA3 was used to study conditions for modifying the efficiency of the inhibitory input. The level of dephosphorylation of GABAa and GABAb receptors, which determines the GABA sensitivity of these receptors, was shown to depend on the Ca(2+)-dependent ratio of active protein kinases and protein phosphatases; the level of dephosphorylation decreased monotonically as the intracellular Ca2+ increased. Posttetanic increases and decreases in the Ca2+ concentration, as compared with the level achieved during the previous stimulation, led to increases or decreases respectively in the number of dephosphorylated GABA receptors and to induction of long-term potentiation and depression, respectively, in the efficiency of inhibitory transmission. The extent of the modification effect depended on the ratio of the quantities of inhibitory and excitatory mediators in the synaptic cleft. At very low or very high GABA concentrations, modification of inhibitory transmission was insignificant.

Contrasting of synaptic signals by simultaneous modification of excitatory and inhibitory inputs.

Conditions facilitating long-term contrasting of interneuronal connections were studied using a mathematical model of posttetanic Ca(2+)-dependent postsynaptic processes in pyramidal neurons of hippocampal field CA3. These studies demonstrated that modified inhibition selectively facilitates. long-term potentiation of the efficiency of one of the interneuronal connections when the presynaptic neuron discharges at a given frequency for a short time, while connections formed from the same postsynaptic cell with other presynaptic neurons undergo long-term depression. The mechanism underlying this contrasting may involve long-term depression of the efficiency of disynaptic inhibitory transmission to the rhythmically stimulated input, even when the efficiency of monosynaptic excitatory transmission at the same input is low and undergoes minimal potentiation. When the "common" inhibitory neuron is simultaneously activated by various presynaptic cells. heterosynaptic potentiation of inhibitory transmission can simultaneously develop at the other inputs of the postsynaptic cell, without change in the efficiency of excitatory transmission, which leads to long-term depression of the efficiency of the connections between other excitatory neurons and the postsynaptic cell.