Trophic actions of GABA on neuronal development

doi:10.1016/j.tins.2005.03.010

Trends in Neurosciences

Volume 28, Issue 6, June 2005, Pages 278-283

https://doi.org/10.1016/j.tins.2005.03.010 Get rights and content

During brain development, transmitter-gated receptors are operative before synapse formation, suggesting that their action is not restricted to synaptic transmission. GABA, which is the principal excitatory transmitter in the developing brain, acts as an epigenetic factor to control processes including cell proliferation, neuroblast migration and dendritic maturation. These effects appear to be mediated through a paracrine, diffuse, non-synaptic mode of action that precedes the more focused, rapid mode of operation characteristic of synaptic connections. This sequential operation implies that GABA is used as an informative agent but in a unique context at an early developmental stage. This sequence also implies that by altering these effects, drugs acting on the GABA system could be pathogenic during pregnancy.

Introduction

Neurotransmitters have central roles in synaptic communication and convey most of the information required for operation of the brain and its networks. However, as is often the case in nature, this device is used more than once. Thus, it is now clear that GABA and glutamate operate before synapse formation (Box 1) and that, in addition to their roles in synapse communication, they have a trophic role in neuronal maturation. Recent studies also suggest that GABA is the first neurotransmitter to become functional in developing networks and provides most of the initial excitatory drive. GABA-mediated mechanisms thus have a central role both in early stages, when networks are non-existent and neurons are an ensemble of immature cells that have little communication, and later, when GABAergic synapses operate and the emerging network generates a coherent pattern of activity. In this respect, GABA provides an excellent example of the multiple forms and actions that a molecule can exert at different developmental stages. This review will examine the roles of GABA, particularly in relation to proliferation, neuronal migration, synapse formation and activity-dependent mechanisms that are essential for network construction.

Section snippets

When GABA modulates progenitor proliferation and survival

In several preparations, GABA agonists exert important but contrasting effects on cell proliferation depending on the type of precursor investigated and the type of animal assayed (e.g. rats versus mice). Thus, GABA inhibits cell-cycle progression of precursors in neurospheres and organotypic striatal slices [1], shortens the cell cycle in cortical slices [2] and decreases DNA synthesis and the number of cells that incorporate bromodeoxyuridine (BrdU) in acute slices [3]. By contrast, GABA

When GABA modulates neuronal migration

Once immature neuroblasts generated in the germinal layers become postmitotic, they start to migrate into the cerebral tissue to reach their targets. In the cerebral cortex there are two different modes of migration – a radial mode for the principal pyramidal cells, and a tangential mode for the interneurons [9]. GABA, acting on several receptor subtypes (of both GABA_A and GABA_B subclasses), modulates migrating neuroblasts as a motility-promoting, an acceleratory or a stop signal 2, 10, 11, 12,

When GABA modulates neuronal arbour elaboration and differentiation

Spoerri [19] proposed GABA as a trophic or regulatory factor having observed that treatment of dissociated embryonic chick cortical and retinal cells using GABA (1 μM) increased the length and branching of the neurites and augmented the density of synapses. This was extended to mammalian neurons by Barbin and co-workers [20], who showed that GABA_A receptor antagonists reduced the dendritic outgrowth of cultured rat hippocampal neurons (Figure 1). Subsequent studies in diverse brain structures,

When the GABA shift is activity dependent

In maturing brain, GABA exerts a depolarizing action related namely to a reverse gradient of Cl⁻. This transient effect is essentially due to a low expression of the neuronal Cl⁻-extruding K⁺/Cl⁻ co-transporter KCC2 [34]. There is general agreement that the GABA switch from excitatory to inhibitory action is mediated by upregulation of the co-transporter KCC2, which extrudes Cl⁻ and has delayed expression [35]. Whether this shift is activity dependent is at present controversial. Ganguly et al.

When knocking-out GADs does not affect brain development

This plethora of actions of GABA stands in contrast to the lack of effects of genetically deleting the enzymes that synthesize GABA. Thus, double knockdown of the GABA-synthesizing enzymes glutamic acid decarboxylase (GAD)65 and GAD67 did not produce discernible disorders of brain histogenesis, including cortical layering [38]. Although this observation might suggest that neurogenesis and cell migration do not require GABAergic systems, it bears stressing that the redundancy in knockout animals

Concluding remarks

Recent observations suggest that GABA has a variety of important functions during maturation. This role is not restricted to GABA because several other transmitters can modulate essential functions in developing brain [40]. The uniqueness of GABA is epitomized by its early operation – before glutamate synapses are functional – indicating that, at least during a restricted period, GABA provides all the excitatory drive. In addition, the possibly activity-dependent shift of GABA actions following

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Trends in Neurosciences

INMED/TINS special issueTrophic actions of GABA on neuronal development

Introduction

Section snippets

When GABA modulates progenitor proliferation and survival

When GABA modulates neuronal migration

When GABA modulates neuronal arbour elaboration and differentiation

When the GABA shift is activity dependent

When knocking-out GADs does not affect brain development

Concluding remarks

Autocrine/paracrine activation of the GABAA receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum

J. Neurosci.

Differential modulation of proliferation in the neocortical ventricular and subventricular zones

J. Neurosci.

GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis

Neuron

GABA induces proliferation of immature cerebellar granule cells grown in vitro

Dev. Brain Res.

Activation of the GABAA receptor inhibits the proliferative effects of bFGF in cortical progenitor cells

Eur. J. Neurosci.

Muscimol-induced death of GABAergic neurons in rat brain aggregating cell cultures

Dev. Brain Res.

GABA promotes survival but not proliferation of parvalbumin-immunoreactive interneurons in rodent neostriatum: an in vivo study with stereology

Neuroscience

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Proc. Natl. Acad. Sci. U. S. A.

Modes of neuronal migration in the developing cerebral cortex

Nat. Rev. Neurosci.

Differential response of cortical plate and ventricular zone cells to GABA as a migration stimulus

J. Neurosci.

GABA inhibits migration of luteinizing hormone-releasing hormone neurons in embryonic olfactory explants

J. Neurosci.

Orchestration of neuronal migration by activity of ion channels, neurotransmitter receptors, and intracellular Ca2+ fluctuations

J. Neurobiol.

Blockade of GABAB receptors alters the tangential migration of cortical neurons

Cereb. Cortex

Environmental factors and disturbances of brain development

Semin. Neonatol.

Do pediatric drugs cause developing neurons to commit suicide?

Trends Pharmacol. Sci.

Prenatal exposure to ethanol alters the postnatal development and transformation of radial glia to astrocytes in the cortex

J. Comp. Neurol.

Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome

Science

Congenital malformations due to antiepileptic drugs

Epilepsy Res.

Neurotrophic effects of GABA in cultures of embryonic chick brain and retina

Synapse

Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons

Neurosci. Lett.

GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABAA receptor activation, calcium influx and CaMKII and ERK1/2 pathways

J. Neurochem.

GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABAA autoreceptor/Cl− channels

J. Neurosci.

Early expression of glycine and GABAA receptors in developing spinal cord neurons. Effects on neurite outgrowth

Neuroscience

GABA as a trophic factor for developing monoamine neurons

Perspect. Dev. Neurobiol.

Activity-dependent remodeling of presynaptic inputs by postsynaptic expression of activated CaMKII

Neuron

Interneurons set the tune of developing networks

Trends Neurosci.

Homeostatic plasticity in the developing nervous system

Nat. Rev. Neurosci.

NMDA receptor activation limits the number of synaptic connections during hippocampal development

Nat. Neurosci.

Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites

Nat. Neurosci.

Ca2+ oscillations mediated by the synergistic excitatory actions of GABAA and NMDA receptors in the neonatal hippocampus

Neuron

The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite

J. Neurosci.

Spontaneous synaptic activity is required for the formation of functional GABAergic synapses in the developing rat hippocampus

J. Physiol.

Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus

J. Neurosci.

The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation

Nature

INMED/TINS special issue
Trophic actions of GABA on neuronal development

Autocrine/paracrine activation of the GABA_A receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum

Activation of the GABA_A receptor inhibits the proliferative effects of bFGF in cortical progenitor cells

Orchestration of neuronal migration by activity of ion channels, neurotransmitter receptors, and intracellular Ca²⁺ fluctuations

Blockade of GABA_B receptors alters the tangential migration of cortical neurons

Involvement of GABA_A receptors in the outgrowth of cultured hippocampal neurons

GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA_A receptor activation, calcium influx and CaMKII and ERK1/2 pathways

GABA expression dominates neuronal lineage progression in the embryonic rat neocortex and facilitates neurite outgrowth via GABA_A autoreceptor/Cl⁻ channels

Early expression of glycine and GABA_A receptors in developing spinal cord neurons. Effects on neurite outgrowth

Ca²⁺ oscillations mediated by the synergistic excitatory actions of GABA_A and NMDA receptors in the neonatal hippocampus

The K⁺/Cl⁻ co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation