The amino acid GABA (γ-aminobutyric acid) was first identified in the mammalian brain over 50 years ago, and during the 1950s and 1960s, strong evidence accumulated that it acts as an inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems.
GABA is synthesized from glutamate and is loaded into synaptic vesicles, from which it is released by calcium-dependent exocytosis. Non-vesicular forms of GABA secretion have also been described, and these might be particularly important during brain development.
In developing neurons, GABA has been shown to act as an excitatory neurotransmitter. This is largely due to a relatively high intracellular chloride concentration in immature neurons, which decreases as development proceeds, allowing GABA to become progressively inhibitory.
The first indication that GABA might act as a trophic substance during nervous system development came from studies showing that GABA could promote neurite growth in the rat superior cervical ganglia. Subsequently, GABA has also been shown to regulate neuronal proliferation and migration in the developing cortex.
Examination of mice with mutations in key genes of the GABA pathway has revealed surprisingly few developmental abnormalities in the central nervous system. However, developing cells might be promiscuous in their use of transmitter signals, so it is possible that any system that induces membrane depolarization could be used to influence developmental programmes.
In the mature brain, GABA (γ-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Goodman, C. S. & Shatz, C. J. Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72, 77–98 (1993).
Edlund, T. & Jessell, T. M. Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system. Cell 96, 211–224 (1999).
Lauder, J. M. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 16, 233–240 (1993).
Levitt, P., Harvey, J. A., Friedman, E., Simansky, K. & Murphy, E. H. New evidence for neurotransmitter influences on brain development. Trends Neurosci. 20, 269–274 (1997).
Meier, E., Hertz, L. & Schousboe, A. Neurotransmitters as developmental signals. Neurochem. Int. 19, 1–15 (1991).
Cameron, H. A., Hazel, T. G. & McKay, R. D. Regulation of neurogenesis by growth factors and neurotransmitters. J. Neurobiol. 36, 287–306 (1998).
Barker, J. L. et al. GABAergic cells and signals in CNS development. Perspect. Dev. Neurobiol. 5, 305–322 (1998).
Morse, D. E., Duncan, H., Hooker, N., Baloun, A. & Young, G. GABA induces behavioral and developmental metamorphosis in planktonic molluscan larvae. Fed. Proc. 39, 3237–3241 (1980).
Elliott, K. A. C. & Jasper, H. H. γ-Aminobutyric acid. Physiol. Rev. 39, 383–406 (1959).
Cowan, W. M. & Kandel, E. R. in Synapses (eds Cowan, W. M., Sudhof, T. C. & Stevens, C. F.) 1–87 (Johns Hopkins Univ. Press, Baltimore and London, 2001).
Awapara, J., Landau, A., Fuerst, F. & Seale, B. L. Free γ-aminobutyric acid in brain. J. Biol. Chem. 187, 35–39 (1950).
Roberts, E. & Frankel, S. γ-Aminobutyric acid in brain: its formation from glutamic acid. J. Biol. Chem. 187, 55–63 (1950).
Roberts, E. in GABA and Benzodiazepine Receptors (ed. Squires, R. F.) 1–21 (CRC, Boca Raton, Florida, 1988).
Elliott, K. A. C. & Florey, E. Factor I-inhibitory factor from brain. J. Neurochem. 1, 181–191 (1956).
Bazemore, A. W., Elliott, K. A. C. & Florey, E. Isolation of factor I. J. Neurochem. 1, 334–339 (1957).
Kravitz, E. A., Kuffler, S. W. & Potter, D. D. γ-Aminobutyric acid and other blocking compounds in crustacea. III. Their relative concentrations in separated motor and inhibitory axons. J. Neurophysiol. 26, 739–751 (1963).
Kravitz, E. A. & Potter, D. D. A further study of the distribution of γ-aminobutyric acid between excitatory and inhibitory axons of the lobster. J. Neurochem. 12, 323–328 (1965).
Otsuka, M., Iverson, L. L., Hall, Z. W. & Kravitz, E. A. Release of γ-aminobutyric acid from inhibitory nerves of lobster. Proc. Natl Acad. Sci. USA 56, 1110–1115 (1966).
Obata, K. The inhibitory action of γ-aminobutyric acid, a probable synaptic transmitter. Int. Rev. Neurobiol. 15, 167–187 (1972).
Purpura, D. P., Girado, M. & Grundfest, H. Selective blockade of excitatory synapses in the cat brain by γ-aminobutyric acid. Science 125, 1200–1202 (1957).
Kuffler, S. W. & Edwards, C. Mechanisms of γ-aminobutyric acid (GABA) action and its relation to synaptic inhibition. J. Neurophysiol. 21, 589–610 (1958).
Kuffler, S. W. Excitation and inhibition in single nerve cells. Harvey Lect. 54, 176–218 (1960).An early review article that discusses inhibitory synaptic transmission. Written by one of the founders of the field.
Boistel, J. & Fatt, P. Membrane permeability change during inhibitory transmitter action in crustacean muscle. J. Physiol. (Lond.) 144, 176–191 (1958).
Takeuchi, A. & Takeuchi, N. On the permeability of the presynaptic terminal of the crayfish neuromuscular junction during synaptic inhibition and the action of γ-aminobutyric acid. J. Physiol. (Lond.) 183, 433–449 (1966).
Krnjevic, K. & Schwartz, S. The action of γ-aminobutyric acid on cortical neurones. Exp. Brain Res. 3, 320–336 (1967).
Dreifuss, J. J., Kelly, J. S. & Krnjevic, K. Cortical inhibition and γ-aminobutyric acid. Exp. Brain Res. 9, 137–154 (1969).
Takeuchi, A. & Takeuchi, N. Localized action of γ-aminobutyric acid on crayfish muscle. J. Physiol. (Lond.) 177, 225–238 (1965).
Bloom, F. E. & Iversen, L. L. Localizing 3H-GABA in nerve terminals of rat cerebral cortex by electron microscopic autoradiography. Nature 229, 628–630 (1971).
Erlander, M. G., Tillakaratne, N. J., Feldblum, S., Patel, N. & Tobin, A. J. Two genes encode distinct glutamate decarboxylases. Neuron 7, 91–100 (1991).
Fon, E. A. & Edwards, R. H. Molecular mechanisms of neurotransmitter release. Muscle Nerve 24, 581–601 (2001).
Attwell, D., Barbour, B. & Szatkowski, M. Nonvesicular release of neurotransmitter. Neuron 11, 401–407 (1993).
Taylor, J. & Gordon-Weeks, P. R. Calcium-independent γ-aminobutyric acid release from growth cones: role of γ-aminobutyric acid transport. J. Neurochem. 56, 273–280 (1991).
Cherubini, E. & Conti, F. Generating diversity at GABAergic synapses. Trends Neurosci. 24, 155–162 (2001).
Hendry, S. H., Schwark, H. D., Jones, E. G. & Yan, J. Numbers and proportions of GABA-immunoreactive neurons in different areas of monkey cerebral cortex. J. Neurosci. 7, 1503–1519 (1987).
Jones, E. G. in The Cortical Neuron (eds Gutnick, M. J. & Mody, I.) 111–122 (Oxford Univ. Press, New York, 1995).
Douglas, R. & Martin, K. in The Synaptic Organization of the Brain (ed. Shepherd, G. M.) 459–509 (Oxford Univ. Press, New York, 1998).
Houser, C. R., Vaughn, J. E., Hendry, S. H. C., Jones, E. G. & Peters, A. in Cerebral Cortex (eds Jones, E. G. & Peters, A.) 63–89 (Plenum, New York, 1984).
Micheva, K. D. & Beaulieu, C. Quantitative aspects of synaptogenesis in the rat barrel field cortex with special reference to GABA circuitry. J. Comp. Neurol. 373, 340–354 (1996).
De Felipe, J., Marco, P., Fairen, A. & Jones, E. G. Inhibitory synaptogenesis in mouse somatosensory cortex. Cereb. Cortex 7, 619–634 (1997).
Connors, B. W. & Gutnick, M. J. Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci. 13, 99–104 (1990).
Gupta, A., Wang, Y. & Markram, H. Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278 (2000).
Anderson, S. A., Eisenstat, D. D., Shi, L. & Rubenstein, J. Interneuron migration from basal forebrain to neocortex: dependence on dlx genes. Science 278, 474–476 (1997).
Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).
Dammerman, R. S., Flint, A. C., Noctor, S. & Kriegstein, A. R. An excitatory GABAergic plexus in developing neocortical layer 1. J. Neurophysiol. 84, 428–434 (2000).
Freund, T. F. & Meskenaite, V. γ-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex. Proc. Natl Acad. Sci. USA 89, 738–742 (1992).
Nicolelis, M. A., Chapin, J. K. & Lin, R. C. Development of direct GABAergic projections from the zona incerta to the somatosensory cortex of the rat. Neuroscience 65, 609–631 (1995).
Grey, E. G. Axo-somatic and axo-dendritic synapses of the cerebral cortex: an electron-microscopic study. J. Anat. 93, 420–433 (1959).
Colonnier, M. Synaptic patterns on different cell types in the different laminae of the cat visual cortex. An electron microscope study. Brain Res. 9, 268–287 (1968).
Bormann, J. Electrophysiology of GABAA and GABAB receptor subtypes. Trends Neurosci. 11, 112–116 (1988).
Connors, B. W., Malenka, R. C. & Silva, L. R. Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J. Physiol. (Lond.) 406, 443–468 (1988).A nice demonstration of biphasic GABA-mediated postsynaptic potentials in neocortical neurons. This study also illustrates that, when exogenous GABA is applied to different cell regions, a range of changes in membrane potential can be produced.
Kaila, K. Ionic basis of GABAA receptor channel function in the nervous system. Prog. Neurobiol. 42, 489–537 (1994).
Bormann, J., Hamill, O. P. & Sakmann, B. Mechanism of anion permeation through channels gated by glycine and γ-aminobutyric acid in mouse cultured spinal neurones. J. Physiol. (Lond.) 385, 243–286 (1987).
Macdonald, R. L. & Olsen, R. W. GABAA receptor channels. Annu. Rev. Neurosci. 17, 569–602 (1994).
Schofield, P. R. et al. Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature 328, 221–227 (1987).
Mehta, A. K. & Ticku, M. K. An update on GABAA receptors. Brain Res. Brain Res. Rev. 29, 196–217 (1999).
McKernan, R. M. & Whiting, P. J. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19, 139–143 (1996).
Mody, I. Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem. Res. 26, 907–913 (2001).
Bormann, J. & Feigenspan, A. GABAC receptors. Trends Neurosci. 18, 515–519 (1995).
Bormann, J. The 'ABC' of GABA receptors. Trends Pharmacol. Sci. 21, 16–19 (2000).
Hill, D. R. & Bowery, N. G. 3H-Baclofen and 3H-GABA bind to bicuculline-insensitive GABAB sites in rat brain. Nature 290, 149–152 (1981).
Bowery, N. G. et al. (−)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283, 92–94 (1980).
Nicoll, R. A. The coupling of neurotransmitter receptors to ion channels in the brain. Science 241, 545–551 (1988).
LeVine, H. III. Structural features of heterotrimeric G-protein-coupled receptors and their modulatory proteins. Mol. Neurobiol. 19, 111–149 (1999).
Kaupmann, K. et al. Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature 386, 239–246 (1997).
Kaupmann, K. et al. GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature 396, 683–687 (1998).
Billinton, A., Upton, N. & Bowery, N. G. GABAB receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum. Br. J. Pharmacol. 126, 1387–1392 (1999).
LoTurco, J. J. & Kriegstein, A. R. Clusters of coupled neuroblasts in embryonic neocortex. Science 252, 563–566 (1991).
LoTurco, J. J., Owens, D. F., Heath, M. J. S., Davis, M. B. E. & Kriegstein, A. R. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15, 1287–1298 (1995).The first indication that GABA-mediated signalling might regulate the proliferation of cortical precursor cells.
Owens, D. F., Boyce, L. H., Davis, M. B. E. & Kriegstein, A. R. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated patch recordings and calcium imaging. J. Neurosci. 16, 6414–6423 (1996).Using the gramicidin-perforated-patch technique in brain slices, this study reveals a developmental shift in , which is dependent on changes in [Cl−]i.
Owens, D. F., Liu, X. & Kriegstein, A. R. Changing properties of GABAA receptor-mediated signaling during early neocortical development. J. Neurophysiol. 82, 570–583 (1999).
Noctor, S. C. et al. Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J. Neurosci. 22, 3161–3173 (2002).
Serafini, R. et al. Initially expressed early rat embryonic GABAA receptor Cl− ion channels exhibit heterogeneous channel properties. Eur. J. Neurosci. 10, 1771–1783 (1998).
Araki, T., Kiyama, H. & Tohyama, M. GABAA receptor subunit messenger RNAs show differential expression during cortical development in the rat brain. Neuroscience 51, 583–591 (1992).
Fritschy, J. M., Paysan, J., Enna, A. & Mohler, H. Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J. Neurosci. 14, 5302–5324 (1994).
Laurie, D. J., Wisden, W. & Seeburg, P. H. The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J. Neurosci. 12, 4151–4172 (1992).
Ma, W. & Barker, J. L. Complementary expressions of transcripts encoding GAD67 and GABAA receptor α4, β1, and γ1 subunits in the proliferative zone of the embryonic rat central nervous system. J. Neurosci. 15, 2547–2560 (1995).
Poulter, M. O., Barker, J. L., O'Carroll, A. M., Lolait, S. J. & Mahan, L. C. Differential and transient expression of GABAA receptor α-subunit mRNAs in the developing rat CNS. J. Neurosci. 12, 2888–2900 (1992).
Poulter, M. O., Barker, J. L., O'Carroll, A. M., Lolait, S. J. & Mahan, L. C. Co-existent expression of GABAA receptor β2, β3 and γ2 subunit messenger RNAs during embryogenesis and early postnatal development of the rat central nervous system. Neuroscience 53, 1019–1033 (1993).
Saxena, N. C. & Macdonald, R. L. Assembly of GABAA receptor subunits: role of the δ subunit. J. Neurosci. 14, 7077–7086 (1994).
Essrich, C., Lorez, M., Benson, J., Fritschy, J. & Luscher, B. Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin. Nature Neurosci. 1, 563–571 (1998).
Hollrigel, G. S. & Soltesz, I. Slow kinetics of miniature IPSCs during early postnatal development in granule cells of the dentate gyrus. J. Neurosci. 17, 5119–5128 (1997).
Dunning, D. D., Hoover, C. L., Soltesz, I., Smith, M. A. & O'Dowd, D. K. GABAA receptor-mediated miniature postsynaptic currents and α-subunit expression in developing cortical neurons. J. Neurophysiol. 82, 3286–3297 (1999).
Mishina, M. et al. Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature 321, 406–411 (1986).
Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).
Singer, J. H. & Berger, A. J. Development of inhibitory synaptic transmission to motoneurons. Brain Res. Bull. 53, 553–560 (2000).
Chen, L., Wang, H., Vicini, S. & Olsen, R. W. The γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics. Proc. Natl Acad. Sci. USA 97, 11557–11562 (2000).
Moss, S. J. & Smart, T. G. Modulation of amino acid-gated ion channels by protein phosphorylation. Int. Rev. Neurobiol. 39, 1–52 (1996).
Mozrzymas, J. W. & Cherubini, E. Changes in intracellular calcium concentration affect desensitization of GABAA receptors in acutely dissociated P2–P6 rat hippocampal neurons. J. Neurophysiol. 79, 1321–1328 (1998).
Van Eden, C. G., Mrzljak, L., Voorn, P. & Uylings, H. B. Prenatal development of GABA-ergic neurons in the neocortex of the rat. J. Comp. Neurol. 289, 213–227 (1989).
Cobas, A., Fairen, A., Alvarez-Bolado, G. & Sanchez, M. P. Prenatal development of the intrinsic neurons of the rat neocortex: a comparative study of the distribution of GABA-immunoreactive cells and the GABAA receptor. Neuroscience 40, 375–397 (1991).
Behar, T. N. et al. GABA stimulates chemotaxis and chemokinesis of embryonic cortical neurons via calcium-dependent mechanisms. J. Neurosci. 16, 1808–1818 (1996).
Jursky, F. & Nelson, N. Developmental expression of GABA transporters GAT1 and GAT4 suggests involvement in brain maturation. J. Neurochem. 67, 857–867 (1996).
Balslev, Y., Saunders, N. R. & Mollgard, K. Synaptogenesis in the neocortical anlage and early developing neocortex of rat embryos. Acta Anat (Basel) 156, 2–10 (1996).
LoTurco, J. J., Blanton, M. G. & Kriegstein, A. R. Initial expression and endogenous activation of NMDA channels in early neocortical development. J. Neurosci. 11, 792–799 (1991).
Haydar, T. F., Wang, F., Schwartz, M. L. & Rakic, P. Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J. Neurosci. 20, 5764–5774 (2000).Experiments in slice culture indicating that GABA receptor activation differentially regulates precursor proliferation in cells of the VZ and the subventricular zone.
Metin, C., Denizot, J. P. & Ropert, N. Intermediate zone cells express calcium-permeable AMPA receptors and establish close contact with growing axons. J. Neurosci. 20, 696–708 (2000).
Soria, J. M. & Valdeolmillos, M. Receptor-activated calcium signals in tangentially migrating cortical cells. Cereb. Cortex 12, 831–839 (2002).
Tyzio, R. et al. The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite. J. Neurosci. 19, 10372–10382 (1999).A clear demonstration of the sequential formation of GABA and glutamate synapses in hippocampal neurons. Evidence is provided that GABA synapses are the first to form.
Khazipov, R. et al. Early development of neuronal activity in the primate hippocampus in utero. J. Neurosci. 21, 9770–9781 (2001).
Agmon, A. & O'Dowd, D. K. NMDA receptor-mediated currents are prominent in the thalamocortical synaptic response before maturation of inhibition. J. Neurophysiol. 68, 345–349 (1992).
Luhmann, H. J. & Prince, D. A. Postnatal maturation of the GABAergic system in rat neocortex. J. Neurophysiol. 65, 247–263 (1991).A detailed study of the developmental changes in GABA-mediated synaptic signalling in neocortical neurons.
Kim, H. G., Fox, K. & Connors, B. W. Properties of excitatory synaptic events in neurons of primary somatosensory cortex of neonatal rats. Cereb. Cortex 5, 148–157 (1995).
Burgard, E. C. & Hablitz, J. J. Developmental changes in NMDA and non-NMDA receptor-mediated synaptic potentials in rat neocortex. J. Neurophysiol. 69, 230–240 (1993).
Agmon, A., Hollrigel, G. & O'Dowd, D. K. Functional GABAergic synaptic connection in neonatal mouse barrel cortex. J. Neurosci. 16, 4684–4695 (1996).
Kilb, W. & Luhmann, H. J. Spontaneous GABAergic postsynaptic currents in Cajal–Retzius cells in neonatal rat cerebral cortex. Eur. J. Neurosci. 13, 1387–1390 (2001).
Hanganu, I. L., Kilb, W. & Luhmann, H. J. Spontaneous synaptic activity of subplate neurons in neonatal rat somatosensory cortex. Cereb. Cortex 11, 400–410 (2001).
Allendoerfer, K. L. & Shatz, C. J. The subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex. Annu. Rev. Neurosci. 17, 185–218 (1994).
Marin-Padilla, M. Cajal–Retzius cells and the development of the neocortex. Trends Neurosci. 21, 64–71 (1998).
Fukuda, A., Mody, I. & Prince, D. A. Differential ontogenesis of presynaptic and postsynaptic GABAB inhibition in rat somatosensory cortex. J. Neurophysiol. 70, 448–452 (1993).
McLean, H. A., Caillard, O., Khazipov, R., Ben-Ari, Y. & Gaiarsa, J. L. Spontaneous release of GABA activates GABAB receptors and controls network activity in the neonatal rat hippocampus. J. Neurophysiol. 76, 1036–1046 (1996).
Gaiarsa, J. L., Tseeb, V. & Ben-Ari, Y. Postnatal development of pre- and postsynaptic GABAB-mediated inhibitions in the CA3 hippocampal region of the rat. J. Neurophysiol. 73, 246–255 (1995).
Fritschy, J. M. et al. GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur. J. Neurosci. 11, 761–768 (1999).
Behar, T. N., Schaffner, A. E., Scott, C. A., Greene, C. L. & Barker, J. L. GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex. Cereb. Cortex 10, 899–909 (2000).Using a slice-culture system, this paper provides evidence that each class of GABA receptor (A, B and C) might influence a different aspect of neuronal migration.
Behar, T. N. et al. GABAB receptors mediate motility signals for migrating embryonic cortical cells. Cereb. Cortex 11, 744–753 (2001).
Maric, D. et al. GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABAA autoreceptor/Cl− channels. J. Neurosci. 21, 2343–2360 (2001).An in vitro study showing that GABA receptor subunit expression changes as cortical cells progress through development. In addition, GABA A receptor activation is shown to regulate the morphological development of cortical neurons through membrane depolarization and increases in [Ca2+]i.
Brock, L. G., Coombs, J. S. & Eccles, J. C. The recording of potentials from motoneurones with an intracellular electrode. J. Physiol. (Lond.) 117, 431–460 (1952).
Coombs, J. S., Eccles, J. C. & Fatt, P. The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory postsynaptic potential. J. Physiol. (Lond.) 130, 326–373 (1955).
Kandel, E. R., Spencer, W. A. & Brinley, F. J. Electrophysiology of hippocampal neurons. 1. Sequential invasion and synaptic organization. J. Neurophysiol. 24, 225–242 (1961).
Fatt, P. & Katz, B. The effect of inhibitory nerve impulses on a crustacean muscle fiber. J. Physiol. (Lond.) 121, 374–389 (1953).
Scharfman, H. E. & Sarvey, J. M. Responses to GABA recorded from identified rat visual cortical neurons. Neuroscience 23, 407–422 (1987).
McCormick, D. A. GABA as an inhibitory neurotransmitter in human cerebral cortex. J. Neurophysiol. 62, 1018–1027 (1989).
Ben-Ari, Y., Cherubini, E., Corradetti, R. & Gaiarsa, J. L. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J. Physiol. (Lond.) 416, 303–325 (1989).Recordings from hippocampal neurons in early postnatal brain slices showing that GABA A -receptor-mediated synaptic transmission drives the production of giant membrane depolarizations. This finding led to the concept that GABA-mediated synaptic signalling is excitatory in the developing brain.
Brickley, S. G., Cull-Candy, S. G. & Farrant, M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. (Lond.) 497, 753–759 (1996).
Chen, G., Trombley, P. Q. & van den Pol, A. N. Excitatory actions of GABA in developing rat hypothalamic neurones. J. Physiol. (Lond.) 494, 451–464 (1996).Using the gramicidin-perforated-patch technique in cultured hypothalamic neurons, this study nicely illustrates the developmental shift in . This study also shows that GABA A receptor activation can directly excite developing neurons.
Wang, Y. F., Gao, X. B. & van den Pol, A. N. Membrane properties underlying patterns of GABA-dependent action potentials in developing mouse hypothalamic neurons. J. Neurophysiol. 86, 1252–1265 (2001).
Gao, X. B. & van den Pol, A. N. GABA, not glutamate, a primary transmitter driving action potentials in developing hypothalamic neurons. J. Neurophysiol. 85, 425–434 (2001).
Rohrbough, J. & Spitzer, N. C. Regulation of intracellular Cl− levels by Na+-dependent Cl− cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor-mediated responses in spinal neurons. J. Neurosci. 16, 82–91 (1996).
Kriegstein, A. R., Suppes, T. & Prince, D. A. Cellular and synaptic physiology and epileptogenesis of developing rat neocortical neurons in vitro. Brain Res. 431, 161–171 (1987).
Wells, J. E., Porter, J. T. & Agmon, A. GABAergic inhibition suppresses paroxysmal network activity in the neonatal rodent hippocampus and neocortex. J. Neurosci. 20, 8822–8830 (2000).
Clayton, G. H., Owens, G. C., Wolff, J. S. & Smith, R. L. Ontogeny of cation-Cl− cotransporter expression in rat neocortex. Brain Res. Dev. Brain Res. 109, 281–292 (1998).
Rivera, C. et al. The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255 (1999).This study provides evidence that the potassium–chloride co-transporter KCC2 is at least partially responsible for the developmental shift in .
Hubner, C. A. et al. Disruption of KCC2 reveals an essential role of K–Cl cotransport already in early synaptic inhibition. Neuron 30, 515–524 (2001).
Blue, M. E. & Parnavelas, J. G. The formation and maturation of synapses in the visual cortex of the rat. II. Quantitative analysis. J. Neurocytol. 12, 697–712 (1983).
Hosokawa, Y., Sciancalepore, M., Stratta, F., Martina, M. & Cherubini, E. Developmental changes in spontaneous GABAA-mediated synaptic events in rat hippocampal CA3 neurons. Eur. J. Neurosci. 6, 805–813 (1994).
Cherubini, E., Gaiarsa, J. L. & Ben-Ari, Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519 (1991).
Ben-Ari, Y., Khazipov, R., Leinekugel, X., Caillard, O. & Gaiarsa, J. L. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci. 20, 523–529 (1997).
Gao, X. B., Chen, G. & van den Pol, A. N. GABA-dependent firing of glutamate-evoked action potentials at AMPA/kainate receptors in developing hypothalamic neurons. J. Neurophysiol. 79, 716–726 (1998).
Lu, T. & Trussell, L. O. Mixed excitatory and inhibitory GABA-mediated transmission in chick cochlear nucleus. J. Physiol. (Lond.) 535, 125–131 (2001).A nice demonstration that even when GABA A -receptor-mediated synaptic responses are themselves excitatory, they still have the ability to inhibit other excitatory inputs.
Wolff, J. R., Joo, F. & Dames, W. Plasticity in dendrites shown by continuous GABA administration in superior cervical ganglion of adult rat. Nature 274, 72–74 (1978).One of the earliest demonstrations that GABA signalling can influence nervous system development.
Wolff, J. R., Joo, F. & Kasa, P. in Neurotrophic Activity of GABA During Development (eds Redburn, D. & Schousboe, A.) 221–252 (Alan R. Liss, New York, 1987).
Redburn, D. & Schousboe, A. (eds) Neurotrophic Activity of GABA During Development (Alan R. Liss, New York, 1987).
Hansen, G. H., Meier, E., Abraham, J. & Schousboe, A. in Neurotrophic Activity of GABA During Development (eds Redburn, D. & Schousboe, A.) 109–138 (Alan R. Liss, New York, 1987).
Meier, E., Belhage, B., Drejer, J. & Schousboe, A. in Neurotrophic Activity of GABA During Development (eds Redburn, D. & Schousboe, A.) 139–159 (Alan R. Liss, New York, 1987).
Spoerri, P. E. Neurotrophic effects of GABA in cultures of embryonic chick brain and retina. Synapse 2, 11–22 (1988).
Spoerri, P. E. & Wolff, J. R. Effect of GABA-administration on murine neuroblastoma cells in culture. I. Increased membrane dynamics and formation of specialized contacts. Cell Tissue Res. 218, 567–579 (1981).
Ben-Ari, Y. Excitatory actions of GABA during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002).
Yuste, R. & Katz, L. C. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6, 333–344 (1991).The first study to show clearly that GABA A receptor activation in early postnatal cortical neurons produces increases in [Ca2+]i.
Lin, M.-H., Takahashi, M. P., Takahashi, Y. & Tsumoto, T. Intracellualr calcium increase induced by GABA in visual cortex of fetal and neonatal rats and its disappearance with development. Neurosci. Res. 20, 85–94 (1994).
Leinekugel, X., Tseeb, V., Ben-Ari, Y. & Bregestovski, P. Synaptic GABAA activation induces Ca2+ rise in pyramidal cells and interneurons from rat neonatal hippocampal slices. J. Physiol. (Lond.) 487, 319–329 (1995).
Antonopoulos, J., Pappas, I. & Parnavelas, J. Activation of the GABAA receptor inhibits the proliferative effects of bFGF in cortical progenitor cells. Eur. J. Neurosci. 9, 291–298 (1997).
Borodinsky, L. N. & Fiszman, M. L. Extracellular potassium concentration regulates proliferation of immature cerebellar granule cells. Brain Res. Dev. Brain Res. 107, 43–48 (1998).
Cui, H. & Bulleit, R. F. Potassium chloride inhibits proliferation of cerebellar granule neuron progenitors. Brain Res. Dev. Brain Res. 106, 129–135 (1998).
Behar, T. N. et al. Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration. J. Neurosci. 19, 4449–4461 (1999).
Barbin, G., Pollard, H., Gaiarsa, J. L. & Ben-Ari, Y. Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons. Neurosci. Lett. 152, 150–154 (1993).
Marty, S., Berninger, B., Carroll, P. & Thoenen, H. GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor. Neuron 16, 565–570 (1996).
Berninger, B., Marty, S., Zafra, F., da Penha Berzaghi, M. & Thoenen, H. GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro. Development 121, 2327–2335 (1995).These two studies (references 155 and 156 ), which used cultured hippocampal neurons, indicate that GABA stimulation regulates BDNF expression, which, in turn, facilitates interneuron development. These effects are observed only early in culture, when GABA A receptor activation produces membrane depolarization and increases in [Ca2+]i.
Ikeda, Y., Nishiyama, N., Saito, H. & Katsuki, H. GABAA receptor stimulation promotes survival of embryonic rat striatal neurons in culture. Brain Res. Dev. Brain Res. 98, 253–258 (1997).
Vicario-Abejon, C., Collin, C., McKay, R. D. & Segal, M. Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. J. Neurosci. 18, 7256–7271 (1998).
Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996).
Leinekugel, X., Medina, I., Khalilov, I., Ben-Ari, Y. & Khazipov, R. Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus. Neuron 18, 243–255 (1997).
Ganguly, K., Schinder, A. F., Wong, S. T. & Poo, M. GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105, 521–532 (2001).This study provides evidence that the shift in is mediated by the activation of GABA A receptors themselves. Experiments using cultured hippocampal neurons show that membrane depolarization and increases in [Ca2+]i that are provided by GABA A receptor activation early in culture ultimately lead to an increase in KCC2 expression.
Ji, F., Kanbara, N. & Obata, K. GABA and histogenesis in fetal and neonatal mouse brain lacking both the isoforms of glutamic acid decarboxylase. Neurosci. Res. 33, 187–194 (1999).This paper shows that mutant mice that lack the ability to synthesize GABA develop a grossly normal-appearing cortex by birth. However, these animals have not yet been subject to rigorous analysis.
Dellovade, T. L. et al. GABA influences the development of the ventromedial nucleus of the hypothalamus. J. Neurobiol. 49, 264–276 (2001).
Asada, H. et al. Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. Biochem. Biophys. Res. Commun. 229, 891–895 (1996).
Kash, S. F. et al. Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc. Natl Acad. Sci. USA 94, 14060–14065 (1997).
Homanics, G. E. et al. Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl Acad. Sci. USA 94, 4143–4148 (1997).
Culiat, C. T. et al. Concordance between isolated cleft palate in mice and alterations within a region including the gene encoding the β3 subunit of the type A γ-aminobutyric acid receptor. Proc. Natl Acad. Sci. USA 90, 5105–5109 (1993).
Culiat, C. T. et al. Deficiency of the β3 subunit of the type A γ-aminobutyric acid receptor causes cleft palate in mice. Nature Genet. 11, 344–346 (1995).
Flint, A. C., Liu, X. & Kriegstein, A. R. Nonsynaptic glycine receptor activation during early neocortical development. Neuron 20, 43–53 (1998).
Varoqueaux, F. et al. Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc. Natl Acad. Sci. USA 99, 9037–9042 (2002).
Verhage, M. et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869 (2000).
Woo, N. S. et al. Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K–Cl cotransporter gene. Hippocampus 12, 258–268 (2002).
Prosser, H. M. et al. Epileptogenesis and enhanced prepulse inhibition in GABAB1-deficient mice. Mol. Cell. Neurosci. 17, 1059–1070 (2001).
Schuler, V. et al. Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABAB responses in mice lacking GABAB1 . Neuron 31, 47–58 (2001).
Blanton, M. G. & Kriegstein, A. R. Appearance of putative amino acid neurotransmitters during differentiation of neurons in embryonic turtle cerebral cortex. J. Comp. Neurol. 310, 571–592 (1991).
Schwartz, M. L. & Meinecke, D. L. Early expression of GABA-containing neurons in the prefrontal and visual cortices of rhesus monkeys. Cereb. Cortex 2, 16–37 (1992).
Gao, W. J., Wormington, A. B., Newman, D. E. & Pallas, S. L. Development of inhibitory circuitry in visual and auditory cortex of postnatal ferrets: immunocytochemical localization of calbindin- and parvalbumin-containing neurons. J. Comp. Neurol. 422, 140–157 (2000).
Zecevic, N. & Milosevic, A. Initial development of γ-aminobutyric acid immunoreactivity in the human cerebral cortex. J. Comp. Neurol. 380, 495–506 (1997).
Jones, E. G. GABA–peptide neurons of the primate cerebral cortex. J. Mind Behav. 8, 519–536 (1987).
We thank T. Weissman and B. Connors for helpful comments on earlier drafts of this manuscript, and K. Owens for her unique contributions.
A term that describes a receptor that exerts its effects through the modulation of ion channel activity.
A term that describes a receptor that exerts its effects through enzyme activation.
- ZONA INCERTA
A thin layer of grey matter that is situated in the dorsal region of the subthalamus.
- WHOLE-CELL RECORDING
A high-resolution electrophysiological recording technique in which a very small electrode tip is sealed onto a patch of cell membrane and, with suction, the membrane patch is ruptured to allow low-resistance electrical access to the cell interior. Electrical currents flowing across the cell membrane can then be recorded, but the ion composition of the cell interior is altered to that of the electrode-filling solution. By contrast, in gramicidin-perforated-patch recordings, suction is not applied to rupture the patch. Instead, gramicidin in the electrode-filling solution creates tiny pores in the membrane patch. The pores allow low-resistance electrical access for whole-cell recording, but do not allow the passage of anions, and so leave [Cl−]i unchanged.
A mechanism of signalling between cells that relies on the diffusion of signalling molecules through the intercellular spaces.
- INTERMEDIATE ZONE
A transient layer in the developing cortex through which neurons migrate on their way from the proliferative zone to the cortical plate. With maturation, this zone is replaced by the subcortical white matter.
A transient layer of cells in the fetal brain that lies beneath the cortical plate.
- MARGINAL ZONE
The embryonic equivalent of layer I. This is the most superficial layer of the developing cortex.
- NEUROBLASTOMA CELLS
An immortalized cell line derived from tumours that arise from the neural crest.
- TRITIATED-THYMIDINE INCORPORATION
An assay in which a radiolabelled form of thymidine is incorporated into the DNA of dividing cells. These cells can then be detected by autoradiography.
An analogue of thymidine that can be incorporated into replicating DNA. It is used to label dividing cells, which can then be detected with an antibody.
- MINIATURE SYNAPTIC POTENTIALS
Synaptic potentials observed in the absence of presynaptic action potentials; they are thought to correspond to the response elicited by a single vesicle of transmitter.
- CLEFT PALATE
A congenital craniofacial defect in which the palatal shelves fail to fuse, leaving an opening in the roof of the mouth.
- CONDITIONAL MUTANT LINES
Mutant mouse lines in which a gene is inactivated in a temporally and/or spatially restricted fashion.
About this article
Cite this article
Owens, D., Kriegstein, A. Is there more to gaba than synaptic inhibition?. Nat Rev Neurosci 3, 715–727 (2002). https://doi.org/10.1038/nrn919
GABA signalling modulates stomatal opening to enhance plant water use efficiency and drought resilience
Nature Communications (2021)
JCI Insight (2021)
Brain Sciences (2021)
Nutritional Neuroscience (2021)
Neuroscience Bulletin (2021)