“Any significance of our paper comes from the fact that it offers a comprehensive comparison of two distinct methods of signaling by GABA – the basis of each process and the varied functional outcomes.”

This is an extensive and timely review of a field that has gathered a certain momentum in recent years. It brings together data showing how variations in the molecular composition of ionotropic receptors for the neurotransmitter GABA affect their biophysical properties and subcellular targeting, enabling them to participate in different forms of signaling.

Rather than describing a new discovery, it presents an overview of a growing literature. We highlight the differences between conventional "phasic" synaptic GABA_A receptor activation and "tonic" activation of extrasynaptic receptors. Such tonic activation occurs in developing or embryonic neurons, before they receive synaptic input, as well as in some mature neurons.

Any significance of our paper comes from the fact that it offers a comprehensive comparison of two distinct methods of signaling by GABA—the basis of each process, and their different functional outcomes.

Nerve cells in the brain transmit information in the form of electrical activity. At junctions between cells, chemicals (neurotransmitters) are released that carry the signal from one cell to the next. By binding to receptors that are clustered at these points of synaptic contact, neurotransmitters usually cause a change in the movement of ions across the membrane of the target cell.

Neurotransmitters may "excite" cells, making it more likely that they fire an action potential; others may "inhibit" target cells and reduce the likelihood that they will fire action potentials. The neurotransmitter GABA (у-aminobutyric acid) falls into this latter class and, among other things, plays a key role in preventing pathological over-excitation of the brain.

In our review we compare the traditional form of synaptic signaling with one in which certain subtypes of GABA receptors, found outside of synapses, can be persistently activated by low concentrations of GABA in the environment of the cells.

The receptors that allow this persistent or "tonic" form of signaling have a different molecular composition and different properties from those located at synapses, which are activated briefly by a pulse of GABA released from the presynaptic cell. Aside from having different effects on their target cells, the receptors that mediate these forms of signaling also respond differently to important classes of drugs such as anesthetics, hypnotics, and, somewhat controversially, alcohol.

I have long been interested in the neurotransmitter GABA. I stumbled into work on tonic receptor activation as a result of a fortuitous observation made while using electrophysiological methods to investigate GABA-mediated neurotransmission in the cerebellum. This early work was performed with Makoto Kaneda—now at the Keio University School of Medicine in Tokyo—and Stuart Cull-Candy at UCL.

Subsequently, I spent a long and fruitful period working on this problem with Stephen Brickley (now at Imperial College London), moving from a basic characterization of the process in cerebellar granule cells, to identification of the GABA_A receptors involved, through studies of transgenic animals in collaboration with Bill Wisden (then at the MRC Laboratory of Molecular Biology in Cambridge, now at the Institute of Medical Sciences, Aberdeen University) and Istvan Mody (UCLA).

My co-author on this review, Zoltan Nusser, is Head of the Laboratory of Cellular Neurophysiology at the Institute of Experimental Medicine in Budapest, Hungary. Zoltan entered this field originally from an anatomical angle, having worked in the laboratory of Peter Somogyi at the MRC Anatomical Neuropharmacology Unit in Oxford on methods allowing the EM localization of GABA_A receptors.