Tonically active GABAA receptors: modulating gain and maintaining the tone

https://doi.org/10.1016/j.tins.2004.03.005Get rights and content

Abstract

GABAA receptors not only respond to the local release of GABA from presynaptic terminals, but can also mediate a persistent ‘tonic current’. This reflects the activation of high-affinity GABAA receptors by ambient GABA concentrations. Tonic GABAA-receptor-mediated signalling occurs in different brain regions, shows cell-type-specific differences in magnitude and pharmacology, and changes during brain development. Some clues to the adaptive significance of this phenomenon are beginning to emerge: in cerebellar granule cells, it alters the gain of transmission of rate-coded sensory information; in the hippocampus, it acts in a cell-type-specific manner to regulate the excitability of the network. Because tonic conductances can be modulated by changes in GABA release and uptake, and by modulators of high-affinity GABAA receptors including neurosteroids, this phenomenon provides a potentially important new window onto neuronal information processing and pathological states such as epilepsy.

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.

References (74)

  • S. Blomfield

    Arithmetical operations performed by nerve cells

    Brain Res.

    (1974)
  • H.P. Robinson et al.

    Injection of digitally synthesized synaptic conductance transients to measure the integrative properties of neurons

    J. Neurosci. Methods

    (1993)
  • E. Salinas et al.

    Gain modulation: a major computational principle of the central nervous system

    Neuron

    (2000)
  • F.S. Chance

    Gain modulation from background synaptic input

    Neuron

    (2002)
  • J.S. Albus

    A theory of cerebellar function

    Math. Biosci.

    (1971)
  • N. Schweighofer

    Unsupervised learning of granule cell sparse codes enhances cerebellar adaptive control

    Neuroscience

    (2001)
  • T.F. Freund

    Interneuron Diversity series: Rhythm and mood in perisomatic inhibition

    Trends Neurosci.

    (2003)
  • J.S. Isaacson

    Local and diffuse synaptic actions of GABA in the hippocampus

    Neuron

    (1993)
  • M. Scanziani

    GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity

    Neuron

    (2000)
  • A. Ruiz

    GABAA receptors at hippocampal mossy fibers

    Neuron

    (2003)
  • W. Volknandt

    Vesicular release mechanisms in astrocytic signalling

    Neurochem. Int.

    (2002)
  • F. Pouille et al.

    Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition

    Science

    (2001)
  • S.R. Cobb

    Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons

    Nature

    (1995)
  • M. Kaneda

    Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum

    J. Physiol.

    (1995)
  • S.G. Brickley

    Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors

    J. Physiol.

    (1996)
  • M.J. Wall et al.

    Development of action potential-dependent and independent spontaneous GABAA receptor-mediated currents in granule cells of postnatal rat cerebellum

    Eur. J. Neurosci.

    (1997)
  • Z. Nusser et al.

    Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells

    J. Neurophysiol.

    (2002)
  • L.S. Overstreet et al.

    Paradoxical reduction of synaptic inhibition by vigabatrin

    J. Neurophysiol.

    (2001)
  • B.M. Stell et al.

    Receptors with different affinities mediate phasic and tonic GABAA conductances in hippocampal neurons

    J. Neurosci.

    (2002)
  • A. Semyanov

    GABA uptake regulates cortical excitability via cell type-specific tonic inhibition

    Nat. Neurosci.

    (2003)
  • D. Bai

    Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons

    Mol. Pharmacol.

    (2001)
  • M. Frerking

    Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • B.M. Stell

    Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • B. Birnir

    Spontaneously opening GABAA channels in CA1 pyramidal neurones of rat hippocampus

    J. Membr. Biol.

    (2000)
  • Z. Nusser

    Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells

    J. Neurosci.

    (1998)
  • C. Essrich

    Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin

    Nat. Neurosci.

    (1998)
  • J.Y. Yeung

    Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA

    Mol. Pharmacol.

    (2003)
  • Cited by (627)

    View all citing articles on Scopus
    View full text