Trends in Neurosciences
Volume 27, Issue 9, September 2004, Pages 569-575
Journal home page for Trends in Neurosciences

Interneuron Diversity series
Diversity of inhibitory neurotransmission through GABAA receptors

https://doi.org/10.1016/j.tins.2004.07.002Get rights and content

In the brain, highly connected and heterogeneous GABAergic cells are crucial in controling the activity of neuronal networks. They accomplish this task by communicating through remarkably diverse sets of inhibitory processes, the complexity of which is reflected by the variety of interneuron classification schemes proposed in recent years. It is now becoming clear that the subcellular localization and intrinsic properties of heteropentameric GABAA receptors themselves also constitute major sources of diversity in GABA-mediated signaling. This review summarizes some of the factors underlying this diversity, including GABAA receptor subunit composition, localization, activation, number and phosphorylation states, variance of GABA concentration in the synaptic cleft, and some of the presynaptic factors regulating GABA release.

Section snippets

Phasic (synaptic and ’perisynaptic’) inhibition

Synaptic GABAA receptors are anchored by specific proteins [9] of lesser renown than those found at synapses harboring glutamate receptors [10]. Nevertheless, just like glutamate receptors, the number of synaptic GABAA receptors is subject to large alterations during neuronal plasticity and development [11]. Synaptic GABAA receptors usually contain γ subunits, in particular γ2 [11], which is a key factor for benzodiazepine sensitivity [12]. Phasic (synaptic) GABA-mediated transmission 13, 14, 15

Tonic inhibition

Many cells display tonic currents activated by the near-micromolar GABA levels [21] always present in the extracellular space. The charge carried by the activation of tonically active GABAA receptors can be more than three times larger than that produced by phasic inhibition, even when the frequency of phasic events is large 22, 23, 24 (Figure 1). Experimental and theoretical studies indicate that a tonic GABA conductance produces a shunt that affects excitability and gain control [6]. Perhaps

Subunit composition of synaptic GABAA receptors

GABAA receptors are pentameric hetero-oligomers assembled from members of seven different subunit classes, some of which have multiple members: α(1–6), β(1–3), γ(1–3), δ, ε, θ and π [12]. In theory, a bewildering array of various combinations could assemble from these many subunits and their splice variants. However, GABAA receptor subunits do form preferred assemblies, with perhaps dozens of distinct subunit combinations actually present in the brain [12]. Studies in expression systems have

Concluding remarks

Many sources of physiological diversity have been discovered at GABA synapses (Figure 3), and it is likely that the list will grow. Will it be possible to identify the functional consequences of this diversity, and to what end will such information be useful? There is even more complexity because functional diversity per se can translate into higher-level network properties, when population variance as well as mean parameter values determine the behavior of interconnected neurons [68]. In fact,

References (71)

  • G. Sperk

    GABAA receptor subunits in the rat hippocampus.1. Immunocytochemical distribution of 13 subunits

    Neuroscience

    (1997)
  • R.A. Pearce

    Physiological evidence for two distinct GABAA responses in rat hippocampus

    Neuron

    (1993)
  • R.I. Wilson

    Presynaptic specificity of endocannabinoid signaling in the hippocampus

    Neuron

    (2001)
  • T.F. Freund

    Interneuron Diversity series: Rhythm and mood in perisomatic inhibition

    Trends Neurosci.

    (2003)
  • M.V. Jones et al.

    The impact of receptor desensitization on fast synaptic transmission

    Trends Neurosci.

    (1996)
  • S.C. Harney et al.

    Pre- and postsynaptic properties of somatic and dendritic inhibition in dentate gyrus

    Neuropharmacology

    (2002)
  • Z. Nusser

    Differences in synaptic GABAA receptor number underlie variation in GABA mini amplitude

    Neuron

    (1997)
  • M.A. Woodin

    Coincident pre- and postsynaptic activity modifies GABAergic synapses by postsynaptic changes in Cl transporter activity

    Neuron

    (2003)
  • N. Brandon

    Multiple roles of protein kinases in the modulation of gamma-aminobutyric acid(A) receptor function and cell surface expression

    Pharmacol. Ther.

    (2002)
  • J.T. Kittler et al.

    Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition

    Curr. Opin. Neurobiol.

    (2003)
  • Q. Wang

    Control of synaptic strength, a novel function of Akt

    Neuron

    (2003)
  • P. Parra

    How many subtypes of inhibitory cells in the hippocampus?

    Neuron

    (1998)
  • R.S. Sloviter

    Localization of GABAB (R1) receptors in the rat hippocampus by immunocytochemistry and high resolution autoradiography, with specific reference to its localization in identified hippocampal interneuron subpopulations

    Neuropharmacology

    (1999)
  • A.L. Barabási

    Linked

    (2002)
  • T.F. Freund et al.

    Interneurons of the hippocampus

    Hippocampus

    (1996)
  • Q. Xu

    Cortical interneuron fate determination: diverse sources for distinct subtypes?

    Cereb. Cortex

    (2003)
  • Z. Nusser

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

    J. Neurosci.

    (1998)
  • W. Wei

    Perisynaptic localization of δ subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus

    J. Neurosci.

    (2003)
  • S.J. Moss et al.

    Constructing inhibitory synapses

    Nat. Rev. Neurosci.

    (2001)
  • M. Sheng et al.

    Postsynaptic signaling and plasticity mechanisms

    Science

    (2002)
  • W. Sieghart et al.

    Subunit composition, distribution and function of GABAA receptor subtypes

    Curr. Top. Med. Chem.

    (2002)
  • J.W. Mozrzymas

    Modulation of GABAA receptors by hydrogen ions reveals synaptic GABA transient and a crucial role of the desensitization process

    J. Neurosci.

    (2003)
  • L. Chen

    The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics

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

    (2000)
  • A. Roepstorff et al.

    Factors contributing to the decay of the stimulus-evoked IPSC in rat hippocampal CA1 neurons

    J. Neurophysiol.

    (1994)
  • U. Tossman

    Regional distribution and extracellular levels of amino acids in rat central nervous system

    Acta Physiol. Scand.

    (1986)
  • Cited by (0)

    View full text