Journal Article

Nanodomain coupling explains Ca2+ independence of transmitter release time course at a fast central synapse

Jonas, Peter, Arai, Itaru

2014

Overview

A puzzling property of synaptic transmission, originally established at the neuromuscular junction, is that the time course of transmitter release is independent of the extracellular Ca2+ concentration ([Ca2+]o), whereas the rate of release is highly [Ca2+]o-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca2+]o. Modeling of Ca2+-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca2+ channels and release sensors. Experiments with exogenous Ca2+ chelators reveal that channel-sensor coupling at basket cell-Purkinje cell synapses is very tight, with a mean distance of 10–20 nm. Thus, tight channel-sensor coupling provides a mechanistic explanation for the apparent [Ca2+]o independence of the time course of release. The nervous system sends information around the body in the form of electrical signals that travel through cells called neurons. However, these electrical signals cannot cross the synapses between neurons. Instead, the information is carried across the synapse by molecules called neurotransmitters. Calcium ions control the release of neurotransmitters. There is a high concentration of calcium ions outside the neuron but they are not able to pass through the cell membrane under normal conditions. However, when an electrical impulse reaches the synapse, ion channels in the membrane open and allow calcium ions to enter the cell. Once inside, the ions activate the release of neurotransmitters by binding to proteins called release sensors. Several experiments on the release of neurotransmitters have studied the synapses between neurons and muscle fibers. These studies found that the higher the concentration of ions outside the neuron, the higher the rate at which the neurotransmitters were released. However, the timing of release—the length of time over which the neurotransmitters were released—did not depend on the concentration of calcium ions. Arai and Jonas have now studied neurotransmitter release at a synapse in a region of the brain called the cerebellum. These experiments also found that the timing of the release did not depend on the ion concentration, suggesting that this may be a general property of neurotransmitter release. To find out more, Arai and Jonas created a mathematical model of neurotransmitter release. This model suggests that for the timing of release to remain the same, the ion channel and the release sensor must be located close together in the presynaptic terminal. If they are not close together, the timing of release becomes blurred and more dependent on the external calcium concentration. Further experiments confirm the prediction of the model by showing that the calcium channels and the release sensors in these synapses are very close together. The next challenge will be to find out whether the conclusions are also valid for other synapses where the calcium channels and release sensors are further apart.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Ca2+ channel / Calcium (extracellular) / Calcium - metabolism / Calcium channels / Calcium Channels - metabolism / cerebellar basket cell / Cerebellum - metabolism / Chelating agents / Experiments / Female / GABAergic synapse / Male / Mice, Inbred C57BL / Models, Neurological / nanodomain coupling / Neuroscience / Neurotransmitter Agents - metabolism / Neurotransmitter release / Ordinary differential equations / Partial differential equations / Purkinje Cells - metabolism / release sensor / Sensors / Short Report / Synapses / Synapses - metabolism / Synaptic transmission / time course of transmitter release / Time Factors / Transmitters