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Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors

Abstract

In the postnatal subventricular zone (SVZ), local cues or signaling molecules released from neuroblasts limit the proliferation of glial fibrillary acidic protein (GFAP)-expressing progenitors thought to be stem cells. However, signals between SVZ cells have not been identified. We show that depolarization of neuroblasts induces nonsynaptic SNARE-independent GABAA receptor currents in GFAP-expressing cells, the time course of which depends on GABA uptake in acute mouse slices. We found that GABAA receptors are tonically activated in GFAP-expressing cells, consistent with the presence of spontaneous depolarizations in neuroblasts that are sufficient to induce GABA release. These data demonstrate the existence of nonsynaptic GABAergic signaling between neuroblasts and GFAP-expressing cells. Furthermore, we show that GABAA receptor activation in GFAP-expressing cells limits their progression through the cell cycle. Thus, as GFAP-expressing cells generate neuroblasts, GABA released from neuroblasts provides a feedback mechanism to control the proliferation of GFAP-expressing progenitors by activating GABAA receptors.

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Figure 1: GFAP-expressing cells in the SVZ express functional GABAARs.
Figure 2: GABA and picrotoxin affinities for GABAARs in GFAP-expressing cells of the SVZ.
Figure 3: Electrical stimulation of SVZ progenitors evoked nonsynaptic GABAA currents in GFAP-expressing cells.
Figure 4: GABA release from SVZ progenitors is independent of SNARE.
Figure 5: GABA uptake controls GABAAR activation in GFAP-expressing cells of the SVZ.
Figure 6: Near-physiological depolarization of SVZ progenitors induces activation of GABAARs in GFAP-expressing cells that are also tonically activated.
Figure 7: Neuroblasts release GABA spontaneously and upon depolarization.
Figure 8: GABAAR activation limits the proliferation of GFAP-expressing cells.

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Acknowledgements

We thank C. Broberger, J. Fitzpatrick, U. Misgeld, M. Sarkisian, S. Titz and A. Williamson for valuable comments on the manuscript. We thank C.A. Greer for providing us with a scanning confocal microscope. This work was supported by a grant from the National Multiple Sclerosis Society (A.B.) and the US National Institutes of Health (NS042189 and NS048256; A.B.).

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Correspondence to Angélique Bordey.

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Supplementary information

Supplementary Fig. 1

Morphology of striatal astrocytes close to the SVZ border. (PDF 636 kb)

Supplementary Fig. 2

GFAP-expressing cells of the postnatal SVZ do not express synapsin I. (PDF 4422 kb)

Supplementary Fig. 3

Model of GABAergic signaling between neuroblasts and GFAP-expressing cells. (PDF 476 kb)

Supplementary Methods (PDF 76 kb)

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Liu, X., Wang, Q., Haydar, T. et al. Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat Neurosci 8, 1179–1187 (2005). https://doi.org/10.1038/nn1522

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