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Is there more to gaba than synaptic inhibition?

Key Points

  • 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.

Abstract

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.

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Figure 1: Components of the GABA signalling pathway.
Figure 2: Physiological responses to GABA differ in precursor cells and immature neurons.
Figure 3: Developmentally regulated changes in GABA actions in the cortical circuitry.
Figure 4: A developmental shift in GABA actions occurs as a result of changing intracellular chloride concentration.
Figure 5: Non-synaptic actions of GABA might include modulation of proliferation, migration and differentiation.
Figure 6: Effects of GABA on neuronal differentiation depend on GABA-induced membrane depolarization.

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Acknowledgements

We thank T. Weissman and B. Connors for helpful comments on earlier drafts of this manuscript, and K. Owens for her unique contributions.

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Correspondence to Arnold R. Kriegstein.

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DATABASES

LocusLink

BDNF

GABAA receptors

GABAB receptors

GABAC receptor

GABA-T

GAD65

GAD67

GATs

KCC2

NKCC1

VGAT

FURTHER INFORMATION

Encyclopedia of Life Sciences

amino acid neurotransmitters

amino acid transporters

chloride channels

GABAA receptors

GABAB receptors

Glossary

IONOTROPIC

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

METABOTROPIC

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.

PARACRINE

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.

SUBPLATE

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.

5-BROMODEOXYURIDINE

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.

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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

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