Presynaptic Ca2+ Dynamics, Ca2+ Buffers and the Mechanisms of Facilitation

New Jersey Institute Of Technology, Newark NJ

Investigators

Abstract

Using computational modeling, the investigator studies the spatiotemporal dynamics of intracellular calcium influx, diffusion and buffering in a synaptic terminal. The particular phenomenon explored by the investigator is the short-term facilitation of synaptic response, that is, the transient increase in synaptic strength elicited with just a few action potentials, and decaying on time scales of tens to hundreds of milliseconds. Facilitation is observed in a wide variety of systems, and must play an important role in neural dynamics and information processing. Although facilitation is known to depend on the presynaptic accumulation of residual calcium, its precise mechanisms are still under debate. The investigator focuses on the role of endogenous calcium buffers in several different mechanisms previously proposed to explain facilitation. Among such mechanisms is buffer saturation, recently shown experimentally to underlie facilitation at certain central synapses, and a facilitation model relying on both free and bound residual calcium. The study concentrates on two model systems that have been widely used to explore the mechanisms of synaptic transmission: the crayfish neuromuscular junction and the auditory calyx of Held synapse. The abundance of experimental data obtained at these synapses allows detailed modeling of the calcium-secretion coupling. One of the main goals of this study is to explore how variations in endogenous buffering characteristics affect the spatiotemporal calcium concentration profile during trains of action potentials. This in turn helps in elucidating the mechanisms of facilitation and in ascertaining the role of calcium buffers in these and other synapses. Another objective of this work is to estimate the properties of endogenous buffers at the crayfish NMJ and at the calyx of Held. A modeling approach is indispensable in this respect: apart from the over-all buffering capacity, the specific buffering properties are inaccessible to direct measurement at most synapses. The investigator applies computational tools to the study of a fundamental biological process, that of the movement of calcium ions inside a cell. It is known that calcium regulates a vast number of crucial biological events, such as gene transcription, muscle contraction, immune system response, and many others. In order to understand how a single element can regulate such a diverse set of biological reactions, it is necessary to know in detail how calcium concentration is controlled inside a cell. This is particularly important for a better understanding of synaptic transmission, which is at the center of the investigator's work. In synaptic transmission, the entry of calcium into the synapse causes the release of a neurotransmitter chemical, binding of which to the receptors of the neighboring neuron allows the electric activity to be transmitted from one cell to the next. This is the fundamental process of communication between neurons in the nervous system. It is interesting that the strength of the synaptic connection between two neurons does not remain the same, but is constantly changing. The investigator explores how the accumulation of calcium causes some synapses to temporarily increase (facilitate) their strength. Along with other forms of synaptic change (termed synaptic plasticity), such facilitation must play an important role in the functioning of the nervous system. Apart from the immediate goal of further elucidating the synaptic transmission mechanisms, this study of intracellular calcium dynamics helps to shed light on other important biological processes that are also controlled by calcium. Finally, this work contributes to the widening of the use of computational methods in biosciences, which is necessary in order to maintain the current rapid progress in biology.