Stochastic models of invaginating spine synapse with Byzov's ephaptic feedback


A feedback due to an ephaptic effect of the synaptic current on a presynaptic terminal was originally hypothesised by A.L.Byzov for invaginating chemical synapses between photoreceptors and secondary neurons in the retina1. The hypothesis suggests that transmitter release is determined by a potential at the presynaptic membrane. This potential may deviate from the resting potential of the presynaptic neuron in case of deeply invaginating synapses due to the potential drop across the synaptic cleft produced by the postsynaptic current. Therefore, the latter influences the potential at the presynaptic membrane. This creates a feedback, which is positive in case of excitatory chemical synapses. The ephaptic feedback hypothesis provides explanations for some features of synaptic transmission between neurons with sustained activity2-4. The hypothesis, even without strict formalisation, appeared also to be useful for the explanation of some effects in spiking neurons5. Here, we propose two two formalised stochastic models of synaptic transmission incorporating the ephaptic feedback.

The synapse was supposed to contain several release sites. Neurotransmitter release was taken to be random, the release probability being considered exponentially dependent on the potential at the presynaptic membrane, Vp . Each site was suggested to release only one transmitter quantum per each presynaptic spike. The action of the intrasynaptic ephaptic feedback was simulated according to the following scenario. The arrival of a spike depolarizes a presynaptic terminal. Consequently the release probability of all sites abruptly increases, and at some time point, some site releases a portion of transmitter. The transmitter gets bound with receptors at the subsynaptic membrane and activates receptor channels. This generates an excitatory postsynaptic current (EPSC) flowing through the subsynaptic membrane and creating a potential drop across the synaptic cleft. The value of the potential drop can be calculated from the value of the potential that clamps the postsynaptic neuron, V2 , and from the parameters of the voltage divider (the subsynaptic resistance, Rs , of the receptor zone under the release sites at the given moment and the resistance of the synaptic cleft, Rg). In case the postsynaptic neuron is hyperpolarized, the potential drop across the synaptic cleft causes an additional depolarization of the presynaptic membrane, thus increasing the release probability of the other sites. Such positive feedback evokes a growing depletion of sites that is limited in time by the duration of the spike in the presynaptic terminal. The larger the postsynaptic hyperpolarization, the larger number of presynaptic sites releases transmitter during the spike. On the contrary, a depolarization of the postsynaptic neuron results in a hyperpolarization of the presynaptic membrane thus decreasing neurotransmitter release.

Quantitative manifestations of the intrasynaptic ephaptic feedback depend on specific values of parameters of the synapse. The main purpose of the project was to develop computer models of the intrasynaptic ephaptic feedback, in which a user can edit the parameter values and observe their influence on behavior of the synapse. Two such models are currently under construction. The models are designed as Windows applications, their preliminary versions being available here:

Application eqUNO is destined as an initial step and is recommended for inexperienced users. It simulates responses of the synapse with ephaptic feedback to arrival of a single spike to a presynaptic terminal.
Application eqDUO expands the ephaptic feedback model for the case of paired presynaptic stimulation. It is recommended for advanced users only. It contains twice as many windows and twice as many parameters for editing as compared to eqUNO. Thus, it includes parameters describing temporary changes in release probability resulting from previous transmitter release which are responsible for paired pulse depression and facilitation.

Though the models pursue mainly didactic purposes, they give a number of predictions that could not be easily envisioned and can be tested in physiological experiments.

Literature

1. Byzov A.L. and Trifonov Yu.A. (1968) Hypothesis on the electrical feedback in synaptic transmission between photoreceptors and second-order neurones in vertebrate retina (in Russian). In: Synaptic Processes (ed. P.G.Kostyuk). Kiev: "Naukova Dumka", pp. 231-248

2. Byzov A.L. and Shura-Bura T.M. (1986) Electrical feedback mechanism in the processing of signals in the outer plexiform layer of the retina. Vision Res. 26, 33-34

3. Maximov V.V. and Byzov A.L. (1996) Horizontal cell dynamics: What are the main factors? Vision Res. 36, 4077-4087

4. Byzov A.L. and Maximov V.V. (1998) Electrical feedback in chemical synapses (in Russian). Russian J. Physiol. 84, 1074-1084

5. Voronin L.L., Byzov A.L., Kleschevnikov A.M., Kozhemyakin M., Kuhnt U. and Volgushev M. (1995) Neurophysiological analysis of long-term potentiation in mammalian brain. Behav. Brain Res. 66, 45-52

6. Voronin L.L. (1999/2000) Intrasynaptic ephaptic feedback in central synapses. Neurosci. Behav. Physiol. 30, 575-585 (Translated from Russian J. Physiol. 85, 729-742)

7. Voronin L.L., Volgushev M., Sokolov M., Kasyanov A., Chistiakova M, and Reymann K.G, (1999). Evidence for an electrical feedback in cortical synapses: postsynaptic hyperpolarization alters the number of response failures and quantal content. Neuroscience 92, 399-405

8. Berretta N., Rossokhin A.V., Kasyanov A.M., Sokolov M.V., Cherubini E. and Voronin L.L. (2000) Postsynaptic hyperpolarization increases the strength of AMPA mediated synaptic transmission at large synapses between mossy fibers and CA3 pyramidal cells. Neuropharmacology 39, 2288-2301.

9. Kasyanov A.M., Maximov V.V., Byzov A.L., Berretta N., Sokolov M.V., Gasparini S., Cherubini E., Reymann K. and Voronin L.L. (2000) Differences in amplitude-voltage relations between minimal and composite mossy fibre responses of rat CA3 hippocampal neurons support the existence of intrasynaptic ephaptic feedback in large synapses. Neuroscience 101, 323-336

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Last Update: 22 August, 2003