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

Key Points

  • The sculpting of neuronal connections during brain development depends on a precise balance between inhibition and excitation — an excess of GABA (γ-aminobutyric acid)-mediated inhibition might prevent growth or synapse formation, whereas an excess of glutamatergic excitation could lead to toxicity. This review describes a sequence of events that might provide a solution. First, GABA is initially excitatory. Second, GABA synapses are formed before glutamatergic ones. Third, the excitatory actions of GABA generate a primitive pattern of activity, which helps to modulate neuronal growth and synapse formation.

  • Activation of GABA synapses in young neurons produces depolarization instead of the characteristic hyperpolarization, because of a relatively high concentration of intracellular chloride ions ([Cl]i). The intracellular accumulation of chloride seems to be generated by a delay in the expression of the chloride exporter KCC2.

  • GABA-expressing interneurons become postmitotic at an earlier stage than glutamatergic pyramidal neurons, and they originate from a different source and follow a different migration pathway. In the rodent hippocampus in utero, all the activity is provided by GABA synapses that are formed between interneurons, and the first glutamatergic synapses are also established on GABA interneurons.

  • Early ongoing activity in the brain is dominated by long-lasting, recurrent potentials known as giant depolarizing potentials (GDPs). The excitatory actions of GABA have a central role in the generation of GDPs. GDPs are key players in the modulation by electrical activity of various functions, including neuronal migration and growth, synapse formation and plasticity of developing GABA synapses.

  • The formation of excitatory GABA synapses and the GABA–glutamate developmental sequence have been conserved throughout evolution, and they might constitute a fundamental step in the construction of a functional cortical network and in its reinforcement by neuronal activity.

Abstract

In the immature brain, GABA (γ-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation while avoiding the potentially toxic effects of a mismatch between GABA-mediated inhibition and glutamatergic excitation. As key elements of this cascade are activity dependent, the formation of inhibition adds an element of nurture to the construction of cortical networks.

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Figure 1: Early expression of NKCC1 and late expression of KCC2 determines developmental changes in [Cl]i.
Figure 2: Dual excitatory/inhibitory effects of GABA in immature neurons.
Figure 3: Synergistic actions of GABA, NMDA and AMPA receptors in developing neurons.
Figure 4: Sequential formation of GABA and glutamate synapses in the developing primate and rodent hippocampus.
Figure 5: Quantitative description of the sequence of events during the maturation of GABA and glutamate synapses in primate neurons in utero.
Figure 6: Activity-dependent mechanisms modulate early GABA synapses.
Figure 7: Giant depolarizing potentials in developing hippocampal neurons.

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Acknowledgements

I am grateful to K. Staley, H. Gozlan and J. Barker for their criticism, and to P. Gallet for technical and computer support. My work has been supported by funds from the Institut National de la Santé et de la Recherche Médicale and by various grants from the Fondation de la Recherche Médicale, the French Ministry of Research (Actions Concertées Incitatives) and the Regional Council of Provence-Alpes-Côte d'Azur.

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DATABASES

LocusLink

BDNF

GABAA receptors

GAD

KCC2

NKCC1

synaptophysin

FURTHER INFORMATION

Encyclopedia of Life Sciences

amino acid neurotransmitters

amino acid transporters

chloride channels

GABAA receptors

Glossary

IONOTROPIC

A term that describes a receptor that exerts its effects through the modulation of ion channel activity.

RNASE PROTECTION ASSAY

A technique that is used to measure the quantity of messenger RNA that corresponds to a given gene in an RNA sample. A labelled RNA probe that is complementary to the relevant sequence is hybridized with the RNA sample; any RNA that does not hybridize with the probe is then digested away using ribonuclease. The undigested mRNA can then be quantified on an electrophoresis gel.

INPUT RESISTANCE

An estimate of the cell Ohmic resistance (V = IR).

ALLOSTERIC

A term used to describe proteins that have two or more binding sites, in which the occupancy of each site affects the affinities of the others.

STRATUM RADIATUM

A region adjacent to the pyramidal cell layer of hippocampal area CA1. It contains few cell bodies, but is rich in dendrites that project from the pyramidal cells.

DECAY TIME CONSTANT

The initial decay of an excitatory postsynaptic potential (EPSP) can usually be fit by a single exponential function. The time constant derived from this fit describes how quickly an EPSP decays.

THETA ACTIVITY

Rhythmic neural activity with a frequency of 4–8 Hz.

GAMMA ACTIVITY

Rhythmic neural activity with a frequency of 25–70 Hz.

CONDITIONAL POINT MUTATION

A mutation that is expressed at a given developmental stage and/or in a given brain region or neuronal population.

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Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci 3, 728–739 (2002). https://doi.org/10.1038/nrn920

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