Trends in Neurosciences
Tonically active GABAA receptors: modulating gain and maintaining the tone
Section snippets
Where are tonic GABAA-receptor-mediated currents found?
Tonic GABAA-receptor-mediated currents were first described in cerebellar granule cells in voltage-clamp experiments, where application of GABAA receptor antagonists was found to reduce the current required to keep the cell at a fixed potential (the ‘holding current’). This was accompanied by a decrease in the background noise, consistent with block of stochastic ion channel openings 4, 5, 6 (Figure 1a). At about the same time, tonic GABAA receptor activation was also described in embryonic
Do specific GABAA receptor subtypes mediate the tonic current?
Detection of the low extracellular GABA concentrations that persist in the presence of GABA uptake requires high-affinity non-desensitizing receptors. The finding that the tonic conductance can be increased by manipulations that elevate the extracellular GABA concentration implies that the receptors involved are not saturated by ambient neurotransmitter. It is likely, however, that the tonic current is mediated by a heterogeneous population of receptors, with differing GABA affinities.
The role of regional extracellular GABA regulation
The properties of the GABAA receptors, although important, are not the only mechanism that could underlie the cell-type specificity of tonic GABAA receptor conductances. The magnitude of the tonic current depends crucially on the concentration of GABA, as demonstrated by the enhancement of tonic GABAA-receptor-mediated currents by increasing the GABA concentration in the slice perfusate or by inhibiting GABA metabolism or uptake. Local differences in the ambient extracellular GABA concentration
Cell-type-specific development of the tonic current
Tonic GABAA receptor currents are expressed in neuronal progenitor cells, where they might play a part in neural development 7, 27. What about the role and variation of the tonic current during development in differentiated neurons?
In cerebellar granule cells, the tonic GABAA-receptor-mediated conductance increases with maturation 5, 6, while IPSCs become smaller and faster 5, 28. The tonic conductance becomes comparable to the peak amplitude of the phasic component in granule cells in the
Plasticity and modulation
Several recent studies have shown that changes in GABA release can modulate tonic GABAA-receptor-mediated currents. During periods of intense synaptic activity, extracellular GABA concentrations rise [33], potentially increasing the magnitude of the tonic current. This is illustrated by the effect of kainate application, which produces robust firing of interneurons (and thus GABA release), resulting in an increase in tonic GABAA-receptor-mediated currents both in hippocampal pyramidal cells [15]
Effect of tonic inhibition on computations within individual neurons
The membrane conductance plays an important role in neuronal processing because it determines both the voltage response to a current and the membrane time constant. The changes in the membrane time constant and input resistance that occur during changes in tonic inhibition therefore alter the time window over which synaptic integration occurs 11, 41. These alterations in membrane properties can modulate both the conductance threshold (and current threshold) for firing and the firing pattern.
Effects on network excitability
Modulation of neuronal gain and firing threshold are important for maintaining the firing rate within the operational range over a wide range of excitatory drive. This allows cells that have a limited dynamic range to operate over a wide range of network conditions without saturating. For example, if tonic inhibition in the cerebellar granule cell layer changes from one level to another, either through a change in Golgi cell firing or through an action-potential-independent release mechanism,
Concluding remarks
Tonic GABAA-receptor-mediated conductances are large in cerebellar and dentate granule cells and in hippocampal interneurons, but are much smaller or undetectable in pyramidal cells. This cell-type specificity probably reflects differences in the distribution of high-affinity GABAA receptors and the level of receptor expression, and local differences in the extracellular GABA concentration. Tonic inhibition is developmentally regulated and can increase or decrease with age depending on the cell
Acknowledgements
We thank David Attwell and Mark Farrant for helpful comments on the manuscript. R.A.S. is funded by the Wellcome Trust, Medical Research Council and EU.
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