Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 314 (5805): 1610-1613

Copyright © 2006 by the American Association for the Advancement of Science

Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development

Zhaoping Liu, Robert A. Neff, Darwin K. Berg*

Abstract: GABA ({gamma}-aminobutyric acid), the major inhibitory transmitter in the brain, goes through a transitory phase of excitation during development. The excitatory phase promotes neuronal growth and integration into circuits. We show here that spontaneous nicotinic cholinergic activity is responsible for terminating GABAergic excitation and initiating inhibition. It does so by changing chloride transporter levels, shifting the driving force on GABA-induced currents. The timing of the transition is critical, because the two phases of GABAergic signaling provide contrasting developmental instructions. Synergistic with nicotinic excitation, GABAergic inhibition constrains neuronal morphology and innervation. The results reveal a multitiered activity-dependent strategy controlling neuronal development.

Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0357, USA.

* To whom correspondence should be addressed. Email: dberg{at}

Lateral Mobility of Presynaptic {alpha}7-Containing Nicotinic Receptors and Its Relevance for Glutamate Release.
D. Gomez-Varela and D. K. Berg (2013)
J. Neurosci. 33, 17062-17071
   Abstract »    Full Text »    PDF »
Methamidophos Exposure During the Early Postnatal Period of Mice: Immediate and Late-Emergent Effects on the Cholinergic and Serotonergic Systems and Behavior.
C. S. Lima, A. C. Dutra-Tavares, F. Nunes, A. L. Nunes-Freitas, A. Ribeiro-Carvalho, C. C. Filgueiras, A. C. Manhaes, A. Meyer, and Y. Abreu-Villaca (2013)
Toxicol. Sci. 134, 125-139
   Abstract »    Full Text »    PDF »
The dominant functional nicotinic receptor in progenitor cells in the rostral migratory stream is the {alpha}3{beta}4 subtype.
G. Sharma (2013)
J Neurophysiol 109, 867-872
   Abstract »    Full Text »    PDF »
Molecular Physiology of SPAK and OSR1: Two Ste20-Related Protein Kinases Regulating Ion Transport.
K. B. Gagnon and E. Delpire (2012)
Physiol Rev 92, 1577-1617
   Abstract »    Full Text »    PDF »
The Neurobiology of Opiate Motivation.
R. Ting-A-Kee and D. van der Kooy (2012)
Cold Spring Harb Perspect Med 2, a012096
   Abstract »    Full Text »    PDF »
Optimizing Cholinergic Tone Through Lynx Modulators of Nicotinic Receptors: Implications for Plasticity and Nicotine Addiction.
J. M. Miwa, H. A. Lester, and A. Walz (2012)
Physiology 27, 187-199
   Abstract »    Full Text »    PDF »
Glutamatergic Synapse Formation is Promoted by {alpha}7-Containing Nicotinic Acetylcholine Receptors.
A. F. Lozada, X. Wang, N. V. Gounko, K. A. Massey, J. Duan, Z. Liu, and D. K. Berg (2012)
J. Neurosci. 32, 7651-7661
   Abstract »    Full Text »    PDF »
An update on cholinergic regulation of cholecystokinin-expressing basket cells.
C. A. Cea-del Rio, C. J. McBain, and K. A. Pelkey (2012)
J. Physiol. 590, 695-702
   Abstract »    Full Text »    PDF »
Sticking out of the crowd: the molecular identity and development of cholecystokinin-containing basket cells.
E. Keimpema, A. Straiker, K. Mackie, T. Harkany, and J. Hjerling-Leffler (2012)
J. Physiol. 590, 703-714
   Abstract »    Full Text »    PDF »
Regulation of hippocampal inhibitory circuits by nicotinic acetylcholine receptors.
M. Griguoli and E. Cherubini (2012)
J. Physiol. 590, 655-666
   Abstract »    Full Text »    PDF »
Diminished Cerebral Inhibition in Neonates Associated With Risk Factors for Schizophrenia: Parental Psychosis, Maternal Depression, and Nicotine Use.
S. K. Hunter, M. A. Kisley, L. McCarthy, R. Freedman, and R. G. Ross (2011)
Schizophr Bull 37, 1200-1208
   Abstract »    Full Text »    PDF »
{alpha}7-Containing and Non-{alpha}7-Containing Nicotinic Receptors Respond Differently to Spillover of Acetylcholine.
D. Stanchev and P. B. Sargent (2011)
J. Neurosci. 31, 14920-14930
   Abstract »    Full Text »    PDF »
Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer.
A. Becchetti (2011)
Am J Physiol Cell Physiol 301, C255-C265
   Abstract »    Full Text »    PDF »
Expression of GABA Signaling Molecules KCC2, NKCC1, and GAD1 in Cortical Development and Schizophrenia.
T. M. Hyde, B. K. Lipska, T. Ali, S. V. Mathew, A. J. Law, O. E. Metitiri, R. E. Straub, T. Ye, C. Colantuoni, M. M. Herman, et al. (2011)
J. Neurosci. 31, 11088-11095
   Abstract »    Full Text »    PDF »
Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate.
R. Tyzio, C. Allene, R. Nardou, M. A. Picardo, S. Yamamoto, S. Sivakumaran, M. D. Caiati, S. Rheims, M. Minlebaev, M. Milh, et al. (2011)
J. Neurosci. 31, 34-45
   Abstract »    Full Text »    PDF »
Non-cell-autonomous factor induces the transition from excitatory to inhibitory GABA signaling in retina independent of activity.
W. B. Barkis, K. J. Ford, and M. B. Feller (2010)
PNAS 107, 22302-22307
   Abstract »    Full Text »    PDF »
Endogenous Signaling through {alpha}7-Containing Nicotinic Receptors Promotes Maturation and Integration of Adult-Born Neurons in the Hippocampus.
N. R. Campbell, C. C. Fernandes, A. W. Halff, and D. K. Berg (2010)
J. Neurosci. 30, 8734-8744
   Abstract »    Full Text »    PDF »
Lateral Mobility of Nicotinic Acetylcholine Receptors on Neurons Is Determined by Receptor Composition, Local Domain, and Cell Type.
C. C. Fernandes, D. K. Berg, and D. Gomez-Varela (2010)
J. Neurosci. 30, 8841-8851
   Abstract »    Full Text »    PDF »
A potential role for nerve growth factor in regulating the maturation of inhibitory neurotransmission..
D. L. Jones (2010)
J. Neurosci. 30, 6813-6814
   Full Text »    PDF »
How GABA generates depolarization.
N. C. Spitzer (2010)
J. Physiol. 588, 757-758
   Full Text »    PDF »
In the Adult Hippocampus, Chronic Nerve Growth Factor Deprivation Shifts GABAergic Signaling from the Hyperpolarizing to the Depolarizing Direction.
L. Lagostena, M. Rosato-Siri, M. D'Onofrio, R. Brandi, I. Arisi, S. Capsoni, J. Franzot, A. Cattaneo, and E. Cherubini (2010)
J. Neurosci. 30, 885-893
   Abstract »    Full Text »    PDF »
Characterization of Rhythmic Ca2+ Transients in Early Embryonic Chick Motoneurons: Ca2+ Sources and Effects of Altered Activation of Transmitter Receptors.
S. Wang, L. Polo-Parada, and L. T. Landmesser (2009)
J. Neurosci. 29, 15232-15244
   Abstract »    Full Text »    PDF »
Novel Repression of Kcc2 Transcription by REST-RE-1 Controls Developmental Switch in Neuronal Chloride.
M. Yeo, K. Berglund, G. Augustine, and W. Liedtke (2009)
J. Neurosci. 29, 14652-14662
   Abstract »    Full Text »    PDF »
The Potassium Chloride Cotransporter KCC-2 Coordinates Development of Inhibitory Neurotransmission and Synapse Structure in Caenorhabditis elegans.
J. E. Tanis, A. Bellemer, J. J. Moresco, B. Forbush, and M. R. Koelle (2009)
J. Neurosci. 29, 9943-9954
   Abstract »    Full Text »    PDF »
Expression of mutant {beta}2 nicotinic receptors during development is crucial for epileptogenesis.
I. Manfredi, A. D. Zani, L. Rampoldi, S. Pegorini, I. Bernascone, M. Moretti, C. Gotti, L. Croci, G. G. Consalez, L. Ferini-Strambi, et al. (2009)
Hum. Mol. Genet. 18, 1075-1088
   Abstract »    Full Text »    PDF »
Inhibition of 7-containing nicotinic ACh receptors by muscarinic M1 ACh receptors in rat hippocampal CA1 interneurones in slices.
J.-x. Shen, B. Tu, and J. L. Yakel (2009)
J. Physiol. 587, 1033-1042
   Abstract »    Full Text »    PDF »
Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function.
E. X. Albuquerque, E. F. R. Pereira, M. Alkondon, and S. W. Rogers (2009)
Physiol Rev 89, 73-120
   Abstract »    Full Text »    PDF »
Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development.
A. Reynolds, E. Brustein, M. Liao, A. Mercado, E. Babilonia, D. B. Mount, and P. Drapeau (2008)
J. Neurosci. 28, 1588-1597
   Abstract »    Full Text »    PDF »
Prenatal and Adolescent Exposure to Tobacco Smoke Modulates the Development of White Matter Microstructure.
L. K. Jacobsen, M. R. Picciotto, C. J. Heath, S. J. Frost, K. A. Tsou, R. A. Dwan, M. P. Jackowski, R. T. Constable, and W. E. Mencl (2007)
J. Neurosci. 27, 13491-13498
   Abstract »    Full Text »    PDF »
Cell-Autonomous Inhibition of {alpha}7-Containing Nicotinic Acetylcholine Receptors Prevents Death of Parasympathetic Neurons during Development.
M. Hruska and R. Nishi (2007)
J. Neurosci. 27, 11501-11509
   Abstract »    Full Text »    PDF »
GABAA Receptor-Mediated Signaling Alters the Structure of Spontaneous Activity in the Developing Retina.
C.-T. Wang, A. G. Blankenship, A. Anishchenko, J. Elstrott, M. Fikhman, S. Nakanishi, and M. B. Feller (2007)
J. Neurosci. 27, 9130-9140
   Abstract »    Full Text »    PDF »
Dendritic Ca2+ signalling due to activation of {alpha}7-containing nicotinic acetylcholine receptors in rat hippocampal neurons.
D. Fayuk and J. L. Yakel (2007)
J. Physiol. 582, 597-611
   Abstract »    Full Text »    PDF »
Excitatory GABA Action Is Essential for Morphological Maturation of Cortical Neurons In Vivo.
L. Cancedda, H. Fiumelli, K. Chen, and M.-m. Poo (2007)
J. Neurosci. 27, 5224-5235
   Abstract »    Full Text »    PDF »
Reversible inhibition of GABAA receptors by {alpha}7-containing nicotinic receptors on the vertebrate postsynaptic neurons.
J. Zhang and D. K. Berg (2007)
J. Physiol. 579, 753-763
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882