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

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.