The principal action of GABA (γ-aminobutyric acid) in the adult CNS is to increase membrane permeability to chloride and bicarbonate ions. The increase in membrane conductance and hyperpolarization that is associated with the activation of postsynaptic GABA type A (GABAA) receptors following brief exposure to a high concentration of GABA released from presynaptic vesicles underlies what is known as 'phasic' inhibition.
In recent years, it has become evident that GABA receptor activation can also take place in a much less spatially and temporally restricted manner. GABA that escapes from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons, and low concentrations of GABA in the extracellular space can result in the persistent 'tonic' activation of GABAA receptors.
One important function of phasic inhibition is the generation of rhythmic activities in neuronal networks. A notable example is the action of cortical and hippocampal basket cells that innervate the perisomatic regions of pyramidal cells. These interneurons have an essential role in generating and maintaining theta and gamma frequency network oscillations.
Tonic activation of GABAA receptors causes a persistent increase in the cell's input conductance, thereby affecting the magnitude and duration of the voltage response to an injected current. For a given excitatory input, the size and duration of the excitatory postsynaptic potential (EPSP) will be reduced, and the temporal and spatial window over which signal integration can occur will be narrowed, thereby reducing the probability that an action potential will be generated.
The different modes of GABAA receptor activation seem to be determined by the subcellular location and biophysical properties of receptor subtypes. Receptors that contain a γ2 subunit in association with α1, α2 or α3 subunits are the predominant subtypes that mediate phasic synaptic inhibition. Receptors that contain α4, α5 or α6 subunits are predominantly or exclusively extrasynaptic, implying that they are more likely to mediate tonic inhibition.
The macroscopic and microscopic properties of GABAA receptors depend on their subunit composition. The most important biophysical differences between receptors that mediate phasic inhibition and those that have been implicated in tonic inhibition are their affinities for GABA and the speed and extent of their desensitization.
The pattern of phasic inhibition is determined by the number, variety and activity of presynaptic GABA-releasing neurons, but the relationship between neuronal activity and tonic inhibition is less clear. In the hippocampus and cerebellum, changes in presynaptic activity or release can modify the magnitude of the tonic conductance. GABA transporters have an important influence on ambient GABA release, so it is possible that tonic inhibition could also be modulated by changes in uptake.
Many processes modulate GABAA receptor number or function and are likely to be relevant to both phasic and tonic inhibition. Reversible post-translational modifications, such as phosphorylation and palmitoylation, affect both the properties and subcellular location of the receptors. In addition, clustering of GABAA receptors changes both their kinetic behaviour and single-channel conductance.
Just as the biophysical properties of GABAA receptors are determined by their subunit composition, so are their pharmacological properties. Differences in subunit composition between synaptic and extra- or perisynaptic receptors are reflected in differential modulation of phasic and tonic inhibition by benzodiazepine site ligands and other clinically relevant drugs.
The proper functioning of the adult mammalian brain relies on the orchestrated regulation of neural activity by a diverse population of GABA (γ-aminobutyric acid)-releasing neurons. Until recently, our appreciation of GABA-mediated inhibition focused predominantly on the GABAA (GABA type A) receptors located at synaptic contacts, which are activated in a transient or 'phasic' manner by GABA that is released from synaptic vesicles. However, there is growing evidence that low concentrations of ambient GABA can persistently activate certain subtypes of GABAA receptor, which are often remote from synapses, to generate a 'tonic' conductance. In this review, we consider the distinct roles of synaptic and extrasynaptic GABA receptor subtypes in the control of neuronal excitability.
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We thank T. Smart (University College London) for comments on the manuscript, M. Wallner (University of California, Los Angeles) and E. Petrini (Trieste) for sharing data prior to publication, and S. Brickley (Imperial College London) for many helpful discussions during a long collaberation with M.F. M.F.'s research is supported by the Wellcome Trust. Z.N. is the recipient of a Wellcome Trust International Senior Research Fellowship, an International Scholarship from Howard Hughes Medical Institute and a Postdoctoral Fellowship from the Boehringer Ingelheim Fond.
The authors declare no competing financial interests.
- ALTERNATIVE SPLICING
During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.
- PARACRINE SIGNALLING
A signalling process that involves the secretion from a cell of molecules that act on other cells expressing appropriate receptors in the immediate neighbourhood, rather than acting on the same cell (autocrine signalling) or on remote cells (endocrine signalling).
Axon terminals end in various configurations within the neuropil. The most common is en passant or de passage, in which axons make simple synapses as they pass dendrites or cell bodies. By contrast, some axons end in — or produce strings of — enlargements that are often packed with synaptic vesicles. These glomerular-type endings might synapse with large numbers of dendrites. In the cerebellum, each large excitatory mossy fibre terminal contacts dendrites from many granule cells and, together with inhibitory Golgi cell axon terminals, forms a glomerular structure that is wrapped with glia.
- THETA FREQUENCY NETWORK OSCILLATION
Rhythmic neural activity with a frequency of 4–8 Hz.
- GAMMA FREQUENCY NETWORK OSCILLATIONS
Rhythmic neural activity with a frequency of 25–70 Hz.
- COINCIDENCE DETECTION
A situation in which two different subthreshold excitatory inputs are sufficiently closely timed that they summate to trigger the generation of an action potential.
A potent marine neurotoxin that blocks voltage-gated sodium channels. Tetrodotoxin was originally isolated from the tetraodon pufferfish.
The covalent attachment of a palmitate (16-carbon, saturated fatty acid) to a cysteine residue through a thioester bond.
A term originally used to describe enzymes that have two or more receptor sites, one of which (the active site) binds the principal substrate, whereas the other(s) bind(s) effector molecules that can influence the enzyme's biological activity. More generally, it is used to describe the indirect coupling of distinct sites within a protein, mediated by conformational changes.
Refers to agents that enhance memory or other cognitive functions.
- ALCOHOL NON-TOLERANT RATS
(ANT rats). A rat line that has been selectively bred to be highly sensitive to motor impairment after ethanol intake.
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Farrant, M., Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat Rev Neurosci 6, 215–229 (2005). https://doi.org/10.1038/nrn1625
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