Review
GABA sets the tempo for activity-dependent adult neurogenesis

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GABA, a major inhibitory neurotransmitter in the adult brain, activates synaptic and extrasynaptic GABAA receptors, causing hyperpolarization of mature neurons. As in the embryonic nervous system, GABA depolarizes neural progenitors and immature neurons in the adult brain. Several recent studies have suggested that GABA has crucial roles in regulating different steps of adult neurogenesis, including proliferation of neural progenitors, migration and differentiation of neuroblasts, and synaptic integration of newborn neurons. Here, we review recent findings on how GABA regulates adult neurogenesis in the subventricular zone of the lateral ventricles and in the dentate gyrus of the hippocampus. We also discuss an emerging view that GABA serves as a key mediator of neuronal activity in setting the tempo of adult neurogenesis.

Introduction

Activity-dependent structural reorganization is a fundamental mechanism of adult neural plasticity [1]. A striking example of such anatomical change is the functional integration of newly generated neurons in the adult central nervous system (CNS). Since the pioneering work of Altman and colleagues [2], numerous studies have repeatedly demonstrated that active neurogenesis, a process that generates functional neurons from neural progenitor and/or stem cells (NPCs), occurs throughout life in discrete brain regions of all mammals, including humans 3, 4. Adult neurogenesis recapitulates the complete process of neuronal development in a mature CNS environment, from proliferation and neuronal fate specification of NPCs, through differentiation, migration and targeting of neurons, to synaptic integration and survival of new neurons 3, 4. In the olfactory system (Figure 1), NPCs located within the subventricular zone (SVZ) give rise to neuroblasts and immature neurons that migrate significant distances – first tangentially via the rostral migratory stream (RMS) and then radially into the olfactory bulb. These new neurons eventually differentiate into two types of interneuron: granule cells and periglomerular cells. In the dentate gyrus of the hippocampus (Figure 2), NPCs located within the subgranular zone (SGZ), at the border between the granule cell layer and hilar region, generate neuroblasts that migrate into the inner granule cell layer and differentiate into new granule cells. These new neurons send axonal projections through the hilus to the CA3 region, and receive glutamatergic and GABAergic synaptic inputs from the entorhinal cortex and local interneurons (Figure 2b).

Accumulating evidence suggests that different steps of adult neurogenesis are differentially regulated by physiological and pathological stimuli, including an enriched environment, stress, learning and seizures [3]. Although these studies also indicate that neuronal activity is essential for this adult form of structural plasticity [5], how electrical activity directly regulates NPCs and their progeny is largely unknown. Surprisingly GABA, a major inhibitory neurotransmitter in the adult brain, has emerged as a key player regulating multiple steps of adult neurogenesis. Here, we review how GABA regulates the development of NPCs and their neuronal progeny in the adult brain, and discuss a potential role for GABA as a sensor of neuronal activity and as a key regulator of the speed and extent of adult mammalian neurogenesis.

Section snippets

Modes of activation and classic roles of GABA in the adult brain

GABA was identified as the first clear example of an inhibitory neurotransmitter in the mammalian brain during the 1950s [6]. Three types of GABA receptor were subsequently identified [7] (Figure 3). GABAA receptors are bicuculline-sensitive ionotropic receptors that carry primarily Cl and, less efficiently, HCO3. GABAC receptors are related Cl-selective ionotropic receptors that are insensitive to bicuculline. GABAB receptors are G-protein-coupled metabotropic receptors that mediate

Regulation of adult neurogenesis by GABA signaling

Adult neurogenesis seems to recapitulate the neuronal developmental processes of embryonic stages, despite significant differences in the local environment 13, 14, 15, 16. Recent technical advances in using retroviruses and developmentally regulated promoters to drive green fluorescent protein (GFP) expression have enabled visualization of newborn cells in living preparations for physiological characterization [17]. Electrophysiological analysis has revealed the expression of functional GABA

GABA signaling as a sensor of neuronal activity during adult neurogenesis

Neurogenesis is classically thought to be regulated by neuronal activity [46], and many in vivo manipulations that influence electrical activity also affect adult neurogenesis [5]. For example, activation of the mossy-fiber pathway [47] increases hippocampal neurogenesis, whereas partial septohippocampal denervation [48] or lesions of the fimbria and fornix [49] have an opposite effect. Electroconvulsive shock 50, 51 and seizures [52] increase NPC proliferation in the SGZ, and prolonged

Potential mechanisms that underlie GABA-mediated regulation of adult neurogenesis

Little is known about how GABA-mediated stimulation regulates adult neurogenesis. For example, the molecular compositions of the receptors and the downstream signaling pathways have yet to be determined.

Concluding remarks

A traditional view of adult neural plasticity involves only postmitotic neuronal modifications and limited turnover of non-neuronal cells. The discovery of active adult neurogenesis across various mammalian species suggests a greater capacity for plasticity in the mature CNS than was previously imagined. The prospect of stimulating endogenous neurogenesis and integrating transplanted neurons also raises hope for new cell-replacement therapies to repair the mature CNS after injury or

Acknowledgements

We thank Fred Gage, Angelique Bordey, and members of Ming and Song laboratories for comments. Our research is supported by American Heart Association postdoctoral fellowship (to S.G.), by the Klingenstein Fellowship Award in Neuroscience, Whitehall Foundation, Sloan Foundation, March of Dimes and NIH (to G-l.M.), and by NIH, Klingenstein Fellowship Award in Neuroscience, McKnight Scholar Award and the Rett Syndrome Research Foundation (to H.S.).

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