Excitatory actions of gaba during development: the nature of the nurture

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).A description of the three 'rules': GABA is excitatory then inhibitory; GABA-synapse formation precedes glutamatergic-synapse formation; and GDPs are present in neonatal hippocampal neurons. These conclusions are based on intracellular recordings from a large sample of pyramidal neurons from birth to P14.

Obata, K., Oide, M. & Tanaka, H. Excitatory and inhibitory actions of GABA and glycine on embryonic chick spinal neurons in culture. Brain Res. 144, 179–184 (1978).

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).

Khazipov, R., Leinekugel, X., Khalilov, I., Gaiarsa, J. L. & Ben Ari, Y. Synchronization of GABAergic interneuronal network in CA3 subfield of neonatal rat hippocampal slices. J. Physiol. (Lond.) 498, 763–772 (1997).

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).A demonstration of the synergistic actions of GABA and NMDA receptors. Using confocal microscopy to visualize calcium changes, together with single-NMDA-channel recordings, the authors show that GABA alters the affinity of the NMDA channel for magnesium, leading to more calcium influx in immature neurons.

Leinekugel, X. et al. GABA is the principal fast-acting excitatory transmitter in the neonatal brain. Adv. Neurol. 79, 189–201 (1999).

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).

Hollrigel, G. S., Ross, S. T. & Soltesz, I. Temporal patterns and depolarizing actions of spontaneous GABAA receptor activation in granule cells of the early postnatal dentate gyrus. J. Neurophysiol. 80, 2340–2351 (1998).

Berninger, B. et al. GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro. Development 121, 2327–2335 (1995).An illustration of the positive loop: GABA activates BDNF, which enhances GABA actions in immature neurons. The shift from excitation to inhibition correlates with the effects on BDNF expression.

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).The blockade of GABA receptors reduces more efficiently the ongoing activity of hypothalamic neurons than does NMDA- or AMPA-receptor blockade. Perforated-patch recordings show the early excitatory actions of GABA in a developing circuit.

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).

Barker, J. L. et al. GABAergic cells and signals in CNS development. Perspect. Dev. Neurobiol. 5, 305–322 (1998).A nice review of the plethora of actions of GABA during development.

Owens, D. F., Boyce, L. H., Davis, M. B. & 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).

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).Electrical stimulation of neocortical layer 1 results in a GABA A -receptor-mediated PSC in pyramidal neurons. Perforated-patch recording shows that the GABA-releasing layer 1 synapse is excitatory and can trigger action potentials in cortical neurons.

Luhmann, H. J. & Prince, D. A. Postnatal maturation of the GABAergic system in rat neocortex. J. Neurophysiol. 65, 247–263 (1991).

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).

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).

Obrietan, K. & van den Pol, A. GABAB receptor-mediated regulation of glutamate-activated calcium transients in hypothalamic and cortical neuron development. J. Neurophysiol. 82, 94–102 (1999).

Vinay, L. & Clarac, F. Antidromic discharges of dorsal root afferents and inhibition of the lumbar monosynaptic reflex in the neonatal rat. Neuroscience 90, 165–176 (1999).

Serafini, R., Valeyev, A. Y., Barker, J. L. & Poulter, M. O. Depolarizing GABA-activated Cl− channels in embryonic rat spinal and olfactory bulb cells. J. Physiol. (Lond.) 488, 371–386 (1995).In dissociated embryonic spinal cord neurons, micromolar GABA activates chloride channels, which, when open, effectively depolarize cells by ∼30 mV. In cell-attached recordings, opening of a single GABA channel can trigger action potentials.

Wang, J., Reichling, D. B., Kyrozis, A. & MacDermott, A. B. Developmental loss of GABA- and glycine-induced depolarization and Ca2+ transients in embryonic rat dorsal horn neurons in culture. Eur. J. Neurosci. 6, 1275–1280 (1994).

Reichling, D. B., Kyrozis, A., Wang, J. & MacDermott, A. B. Mechanisms of GABA and glycine depolarization-induced calcium transients in rat dorsal horn neurons. J. Physiol. (Lond.) 476, 411–421 (1994).

Ye, J. Physiology and pharmacology of native glycine receptors in developing rat ventral tegmental area neurons. Brain Res. 862, 74–82 (2000).

Eilers, J., Plant, T. D., Marandi, N. & Konnerth, A. GABA-mediated Ca2+ signalling in developing rat cerebellar Purkinje neurones. J. Physiol. (Lond.) 536, 429–437 (2001).

Yuste, R. & Katz, L. C. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6, 333–344 (1991).

Ehrlich, I., Lohrke, S. & Friauf, E. Shift from depolarizing to hyperpolarizing glycine action in rat auditory neurones is due to age-dependent Cl− regulation. J. Physiol. (Lond.) 520, 121–137 (1999).

Kakazu, Y., Akaike, N., Komiyama, S. & Nabekura, J. Regulation of intracellular chloride by cotransporters in developing lateral superior olive neurons. J. Neurosci. 19, 2843–2851 (1999).

Wu, W. L., Ziskind-Conhaim, L. & Sweet, M. A. Early development of glycine- and GABA-mediated synapses in rat spinal cord. J. Neurosci. 12, 3935–3945 (1992).

Reith, C. A. & Sillar, K. T. Development and role of GABAA receptor-mediated synaptic potentials during swimming in postembryonic Xenopus laevis tadpoles. J. Neurophysiol. 82, 3175–3187 (1999).

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).

Saint-Amant, L. & Drapeau, P. Motoneuron activity patterns related to the earliest behavior of the zebrafish embryo. J. Neurosci. 20, 3964–3972 (2000).

Lu, T. & Trussell, L. O. Mixed excitatory and inhibitory GABA-mediated transmission in chick cochlear nucleus. J. Physiol. (Lond.) 535, 125–131 (2001).

Sernagor, E. & Grzywacz, N. M. Spontaneous activity in developing turtle retinal ganglion cells: pharmacological studies. J. Neurosci. 19, 3874–3887 (1999).

Sernagor, E. & Mehta, V. The role of early neural activity in the maturation of turtle retinal function. J. Anat. 199, 375–383 (2001).

Ochi, S. et al. Transient presence of GABA in astrocytes of the developing optic nerve. Glia 9, 188–198 (1993).

Sakatani, K., Black, J. A. & Kocsis, J. D. Transient presence and functional interaction of endogenous GABA and GABAA receptors in developing rat optic nerve. Proc. R. Soc. Lond. B 247, 155–161 (1992).

Kandler, K. & Friauf, E. Development of glycinergic and glutamatergic synaptic transmission in the auditory brainstem of perinatal rats. J. Neurosci. 15, 6890–6904 (1995).

Fukuda, A. et al. Simultaneous optical imaging of intracellular Cl− in neurons in different layers of rat neocortical slices: advantages and limitations. Neurosci. Res. 32, 363–371 (1998).

Kuner, T. & Augustine, G. J. A genetically encoded ratiometric indicator for chloride: capturing chloride transients in cultured hippocampal neurons. Neuron 27, 447–459 (2000).

Barry, P. H. & Lynch, J. W. Liquid junction potentials and small cell effects in patch-clamp analysis. J. Membr. Biol. 121, 101–117 (1991).

Delpire, E. Cation–chloride cotransporters in neuronal communication. News Physiol. Sci. 15, 309–312 (2000).

Fukuda, A. et al. Changes in intracellular Ca2+ induced by GABAA receptor activation and reduction in Cl− gradient in neonatal rat neocortex. J. Neurophysiol. 79, 439–446 (1998).

Yamada, J., Okabe, A., Toyoda, H. & Fukuda, A. Development of GABAergic responses and Cl− homeostasis are regulated by differential expression of cation–Cl− cotransporters: gramicidine-perforated patch clamp and single cell multiplex RT-PCR study. Soc. Neurosci. Abstr. (2002).

Rivera, C. et al. The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255 (1999).

Staley, K. & Smith, R. A new form of feedback at the GABAA receptor. Nature Neurosci. 4, 674–676 (2001).

Owens, D. F. & Kriegstein, A. R. Is there more to GABA than synaptic inhibition? Nature Rev. Neurosci. 3, 715–727 (2002).

Luthi, A., Schwyzer, L., Mateos, J. M., Gahwiler, B. H. & McKinney, R. A. NMDA receptor activation limits the number of synaptic connections during hippocampal development. Nature Neurosci. 4, 1102–1107 (2001).

McKinney, R. A., Capogna, M., Durr, R., Gahwiler, B. H. & Thompson, S. M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nature Neurosci. 2, 44–49 (1999).

Cherubini, E., Martina, M., Scinacalpore, M. & Strata, F. GABA excites neonatal neurones through bicuculline sensitive and insensitive chloride channels. Perspect. Dev. Neurobiol. 5, 289–304 (1998).

Khalilov, I., Dzhala, V., Ben Ari, Y. & Khazipov, R. Dual role of GABA in the neonatal rat hippocampus. Dev. Neurosci. 21, 310–319 (1999).

Verheugen, J. A., Fricker, D. & Miles, R. Noninvasive measurements of the membrane potential and GABAergic action in hippocampal interneurons. J. Neurosci. 19, 2546–2555 (1999).

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).

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).

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).

Khazipov, R., Ragozzino, D. & Bregestovski, P. Kinetics and Mg2+ block of N-methyl-d-aspartate receptor channels during postnatal development of hippocampal CA3 pyramidal neurons. Neuroscience 69, 1057–1065 (1995).

Flint, A. C., Maisch, U. S., Weishaupt, J. H., Kriegstein, A. R. & Monyer, H. NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J. Neurosci. 17, 2469–2476 (1997).

Hutcheon, B., Morley, P. & Poulter, M. O. Developmental change in GABAA receptor desensitization kinetics and its role in synapse function in rat cortical neurons. J. Physiol. (Lond.) 522, 3–17 (2000).

Edwards, D. H. Mechanisms of depolarizing inhibition at the crayfish giant motor synapse. I. Electrophysiology. J. Neurophysiol. 64, 532–540 (1990).

Zhang, S. J. & Jackson, M. B. GABAA receptor activation and the excitability of nerve terminals in the rat posterior pituitary. J. Physiol. (Lond.) 483, 583–595 (1995).

Jackson, M. B. & Zhang, S. J. Action potential propagation and propagation block by GABA in rat posterior pituitary nerve terminals. J. Physiol. (Lond.) 483, 597–611 (1995).

Staley, K. J. & Mody, I. Shunting of excitatory input to dentate gyrus granule cells by a depolarizing GABAA receptor-mediated postsynaptic conductance. J. Neurophysiol. 68, 197–212 (1992).

Ziskind-Conhaim, L. Physiological functions of GABA-induced depolarizations in the developing rat spinal cord. Perspect. Dev. Neurobiol. 5, 279–287 (1998).

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).

Khazipov, R. et al. Early development of neuronal activity in the primate hippocampus in utero. J. Neurosci. 21, 9770–9781 (2001).This paper describes the first recordings from primate central neurons in utero . The GABA–glutamate sequence is also observed in primates, and the shift takes place a few weeks after mid-gestation. The article includes a quantitative analysis of dendritic growth, spine formation, and the sequential establishment of axons, apical and basal dendrites. GDPs provide all the activity until a few days before birth. At this stage, pyramidal neurons have as many as 7,000 spines, which can form elaborate patterns.

Rozenberg, F., Robain, O., Jardin, L. & Ben Ari, Y. Distribution of GABAergic neurons in late fetal and early postnatal rat hippocampus. Brain Res. Dev. Brain Res. 50, 177–187 (1989).

Dupuy, S. T. & Houser, C. R. Developmental changes in GABA neurons of the rat dentate gyrus: an in situ hybridization and birthdating study. J. Comp. Neurol. 389, 402–418 (1997).

Super, H. & Soriano, E. The organization of the embryonic and early postnatal murine hippocampus. II. Development of entorhinal, commissural, and septal connections studied with the lipophilic tracer DiI. J. Comp. Neurol. 344, 101–120 (1994).

Diabira, D., Hennou, S., Chevassus-Au-Louis, N., Ben Ari, Y. & Gozlan, H. Late embryonic expression of AMPA receptor function in the CA1 region of the intact hippocampus in vitro. Eur. J. Neurosci. 11, 4015–4023 (1999).

Soriano, E., Del Rio, J. A., Martinez, A. & Super, H. Organization of the embryonic and early postnatal murine hippocampus. I. Immunocytochemical characterization of neuronal populations in the subplate and marginal zone. J. Comp. Neurol. 342, 571–595 (1994).

Marin, O. & Rubenstein, J. L. A long, remarkable journey: tangential migration in the telencephalon. Nature Rev. Neurosci. 2, 780–790 (2001).An excellent review of the tangential migration of interneurons and their underlying mechanisms and possible implications for the construction of a cortical network.

Hennou, S., Khalilov, I., Diabira, D., Ben-Ari, Y. & Gozlan, H. Early sequential formation of functional GABAA and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus. Eur. J. Neurosci. 16, 197–208 (2002).This paper describes the first recordings and reconstructions of hippocampal interneurons in utero and in early postnatal rats. It shows that the GABA–glutamate sequence also takes place in interneurons, but at an earlier stage than in pyramidal cells.

Gubellini, P., Ben Ari, Y. & Gaiarsa, J. L. Activity- and age-dependent GABAergic synaptic plasticity in the developing rat hippocampus. Eur. J. Neurosci. 14, 1937–1946 (2001).

Caillard, O., Ben Ari, Y. & Gaiarsa, J. L. Mechanisms of induction and expression of long-term depression at GABAergic synapses in the neonatal rat hippocampus. J. Neurosci. 19, 7568–7577 (1999).

Caillard, O., Ben Ari, Y. & Gaiarsa, J. L. Long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus. J. Physiol. (Lond.) 518, 109–119 (1999).

Leinekugel, X. et al. Correlated bursts of activity in the neonatal hippocampus in vivo. Science 296, 2049–2052 (2002).

Khalilov, I. et al. A novel in vitro preparation: the intact hippocampal formation. Neuron 19, 743–749 (1997).

Leinekugel, X., Khalilov, I., Ben Ari, Y. & Khazipov, R. Giant depolarizing potentials: the septal pole of the hippocampus paces the activity of the developing intact septohippocampal complex in vitro. J. Neurosci. 18, 6349–6357 (1998).

Menendez de la Prida, L., Bolea, S. & Sanchez-Andres, J. V. Origin of the synchronized network activity in the rabbit developing hippocampus. Eur. J. Neurosci. 10, 899–906 (1998).

Yuste, R., Nelson, D. A., Rubin, W. W. & Katz, L. C. Neuronal domains in developing neocortex: mechanisms of coactivation. Neuron 14, 7–17 (1995).

Garaschuk, O., Linn, J., Eilers, J. & Konnerth, A. Large-scale oscillatory calcium waves in the immature cortex. Nature Neurosci. 3, 452–459 (2000).

Fellippa-Marques, S., Vinay, L. & Clarac, F. Spontaneous and locomotor-related GABAergic input onto primary afferents in the neonatal rat. Eur. J. Neurosci. 12, 155–164 (2000).

O'Donovan, M. J. & Landmesser, L. The development of hindlimb motor activity studied in the isolated spinal cord of the chick embryo. J. Neurosci. 7, 3256–3264 (1987).

O'Donovan, M. et al. Development of spinal motor networks in the chick embryo. J. Exp. Zool. 261, 261–273 (1992).

Gu, X. & Spitzer, N. C. Breaking the code: regulation of neuronal differentiation by spontaneous calcium transients. Dev. Neurosci. 19, 33–41 (1997).

O'Donovan, M. J. The origin of spontaneous activity in developing networks of the vertebrate nervous system. Curr. Opin. Neurobiol. 9, 94–104 (1999).

Feller, M. B., Butts, D. A., Aaron, H. L., Rokhsar, D. S. & Shatz, C. J. Dynamic processes shape spatiotemporal properties of retinal waves. Neuron 19, 293–306 (1997).

Caillard, O., McLean, H. A., Ben Ari, Y. & Gaiarsa, J. L. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus. J. Neurophysiol. 79, 1341–1348 (1998).

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).

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).

Dreyfus-Brisac, C. & Minkowski, A. Low birth weight and EEG maturation. Electroencephalogr. Clin. Neurophysiol. 26, 638 (1969).

Ellingson, R. J. & Peters, J. F. Development of EEG and daytime sleep patterns in normal full-term infant during the first 3 months of life: longitudinal observations. Electroencephalogr. Clin. Neurophysiol. 49, 112–124 (1980).

Rao, A. & Craig, A. M. Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19, 801–812 (1997).

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).

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).

Anderson, S. A. et al. Mutations of the homeobox genes DLX-1 and DLX-2 disrupt the subventricular zone and differentiation of late born striatal neurons. Neuron 19, 27–37 (1997).

Guillemot, F. & Joyner, A. L. Dynamic expression of the Achaete scute homolog Mash 1 in the developing nervous system. Mech. Dev. 42, 171–185 (1993).

Pleasure, S. J. et al. Cell migration from the ganglionic eminences is required for the development of hippocampal GABAergic interneurons. Neuron 28, 727–740 (2000).

Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).

Parra, P., Gulyas, A. I. & Miles, R. How many subtypes of inhibitory cells in the hippocampus? Neuron 20, 983–993 (1998).

Hume, J. R., Duan, D., Collier, M. L., Yamazaki, J. & Horowitz, B. Anion transport in heart. Physiol Rev. 80, 31–81 (2000).

Baumgarten, C. M. & Fozzard, H. A. Intracellular chloride activity in mammalian ventricular muscle. Am. J. Physiol. 241, C121–C129 (1981).

Liu, S., Jacob, R., Piwnica-Worms, D. & Lieberman, M. (Na + K + 2Cl) cotransport in cultured embryonic chick heart cells. Am. J. Physiol. 253, C721–C730 (1987).

Bowery, N. G. & Brown, D. A. Depolarizing actions of γ-aminobutyric acid and related compounds on rat superior cervical ganglia. Br. J. Pharmacol. 50, 205–218 (1974).

Lorsignol, A., Taupignon, A. & Dufy, B. Short applications of γ-aminobutyric acid increase intracellular calcium concentrations in single identified rat lactotrophs. Neuroendocrinology 60, 389–399 (1994).

Garcia, L., Rigoulet, M., Georgescauld, D., Dufy, B. & Sartor, P. Regulation of intracellular chloride concentration in rat lactotrophs: possible role of mitochondria. FEBS Lett. 400, 113–118 (1997).

Krnjevic, K., Cherubini, E. & Ben-Ari, Y. Anoxia on slow inward currents of immature hippocampal neurons. J. Neurophysiol. 62, 896–906 (1989).

Ben Ari, Y. Developing networks play a similar melody. Trends Neurosci. 24, 353–360 (2001).

Freund, T. F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

Bragin, A. et al. Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat. J. Neurosci. 15, 47–60 (1995).

Verhage, M. et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 864–869 (2000).In this study, knockout of Munc18 abolished vesicular release and was lethal. However, the principal brain structures — the neocortex, thalamus, hippocampus and so on — developed, indicating that vesicular release is not required for the correct construction of brain structures.

Vassilatis, D. K. et al. Evolutionary relationship of the ligand-gated ion channels and the avermectin-sensitive, glutamate-gated chloride channels. J. Mol. Evol. 44, 501–508 (1997).

Wolff, M. A. & Wingate, V. P. Characterization and comparative pharmacological studies of a functional γ-aminobutyric acid (GABA) receptor cloned from the tobacco budworm, Heliothis virescens (Noctuidae:Lepidoptera). Invert. Neurosci. 3, 305–315 (1998).

Shelp, B. J., Bown, A. W. & McLean, M. D. Metabolism and functions of γ-aminobutyric acid. Trends Plant Sci. 4, 446–452 (1999).

Breitkreuz, K. E., Shelp, B. J., Fischer, W. N., Schwacke, R. & Rentsch, D. Identification and characterization of GABA, proline and quaternary ammonium compound transporters from Arabidopsis thaliana. FEBS Lett. 450, 280–284 (1999).

Kathiresan, A., Tung, P., Chinnappa, C. C. & Reid, D. M. γ-Aminobutyric acid stimulates ethylene biosynthesis in sunflower. Plant Physiol. 115, 129–135 (1997).

Gallego, P. P., Whotton, L., Picton, S., Grierson, D. & Gray, J. E. A role for glutamate decarboxylase during tomato ripening: the characterisation of a cDNA encoding a putative glutamate decarboxylase with a calmodulin-binding site. Plant Mol. Biol. 27, 1143–1151 (1995).

Galleschi, L., Floris, C. & Cozzani, I. Variation of glutamate decarboxylase activity and γ-amino butyric acid content of wheat embryos during ripening of seeds. Experientia 33, 1575–1576 (1977).

Perovic, S., Krasko, A., Prokic, I., Muller, I. M. & Muller, W. E. Origin of neuronal-like receptors in Metazoa: cloning of a metabotropic glutamate/GABA-like receptor from the marine sponge Geodia cydonium. Cell Tissue Res. 296, 395–404 (1999).

Wegerhoff, R. GABA and serotonin immunoreactivity during postembryonic brain development in the beetle Tenebrio molitor. Microsc. Res. Tech. 45, 154–164 (1999).

Lee, D. & O'Dowd, D. K. Fast excitatory synaptic transmission mediated by nicotinic acetylcholine receptors in Drosophila neurons. J. Neurosci. 19, 5311–5321 (1999).

Delgado, R., Barla, R., Latorre, R. & Labarca, P. l-Glutamate activates excitatory and inhibitory channels in Drosophila larval muscle. FEBS Lett. 243, 337–342 (1989).

Rosay, P., Armstrong, J. D., Wang, Z. & Kaiser, K. Synchronized neural activity in the Drosophila memory centers and its modulation by amnesiac. Neuron 30, 759–770 (2001).

Leal, S. M. & Neckameyer, W. S. Pharmacological evidence for GABAergic regulation of specific behaviors in Drosophila melanogaster. J. Neurobiol. 50, 245–261 (2002).

Neckameyer, W. S. & Cooper, R. L. GABA transporters in Drosophila melanogaster: molecular cloning, behavior, and physiology. Invert. Neurosci. 3, 279–294 (1998).

Hammond, C. (ed.) Cellular and Molecular Neurobiology 2nd edn (Academic, London, 2001).An excellent textbook that relies on classical experiments to provide an introduction to cellular electrophysiology.