A vision of synaptic transmission between central neurons

A fundamental goal of biological sciences is to develop quantitative descriptions of physiological processes. Receptor-mediated synaptic signal transduction is a key component of brain functions. Despite the accumulation of a plethora of morphological and electrophysiological data as well as many phenomenological formulations describing synaptic events, there is no basic mathematically formulated theory of the central nervous system (CNS) synapse that assigns meaning to experimentally observed structural and functional features of real CNS unitary synapses. The objective of this project, therefore, was to take preliminary steps in establishing such a theory for CNS unitary synapses by developing a formal description of interactions between the continuous intrasynaptic signals generated by the discharge of single synaptic vesicle and n-state Markovian postsynaptic receptors responsive to those signals. Pairs of neurons in the CNS are generally coupled via several unitary synapses. In many cases multiple unit neurons can be activated simultaneously. A question arises how quantal or unitary evoked postsynaptic currents (uePSCs) from different unitary synapses of the same neuron merge into a whole-cell evoked postsynaptic current (ePSC) during synaptic transmission and how intrinsic properties of amplitude distributions of uePSCs and ePSCs correlate with each other. In the CNS it is difficult to isolate and study directly individual synapses, therefore, indirect methods have been developed that allow prediction of the properties of a single synapse on the basis of mathematical consideration of responses obtained from a group of synapses. In some cases, it is equally important to be able to predict the distribution of amplitudes expected from activity of a group of synapses if the amplitude distributions from each member of the group are known. The main goal of the second part of this project was to establish an analytical formulation of the convolutional processes that occur naturally in the functioning brain during the central processing of information at central synapses and to apply this formulation to experimental and simulated data. The analytical formulations developed allowed consideration of the converse problem of deconvolution of ePSC amplitude distributions: this problem was reduced to the problem of obtaining a best fit. Within defined constraints, an optimal fit of ePSC amplitude distributions with the derived formulae allows direct estimation of a unique set of parameters describing the uePSC amplitude distribution as well as the number of synapses involved in generating the ePSCs and the probability of failure of release of quanta at those synapses. In addition, the formulation allowed exploration of the significance of the assumptions of synaptic independence and equivalence that are widely used in synaptic studies. By vision I mean a perspective or a point of view from which to consider a phenomenon. The vision of synaptic transmission in the CNS presented here is built upon several closely related studies and provides novel insights into various aspects of synaptic physiology. These studies introduce an analytical description of sub-processes contributing to the synaptic transmission at a unitary synapse (Uteshev and Pennefather, 1996a, 1996b, 1997) and a novel method of deconvolution which allows obtaining a unique set of the intrinsic unitary synaptic parameters from description of experimentally observed ePSC amplitude distributions (Uteshev et al., 1997).