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The Journal of Neuroscience, April 15, 2003, 23(8):3278

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

Laurent Nguyen¹, Brigitte Malgrange¹, Ingrid Breuskin¹, Lucien Bettendorff¹, Gustave Moonen^{1, 2}, Shibeshih Belachew^{1, 2, *}, and Jean-Michel Rigo^{1, *}

¹ Center for Cellular and Molecular Neurobiology, University of Liège, B-4020 Liège, Belgium, and ² Department of Neurology, University of Liège, C.H.U. Sart Tilman, B-4000 Liège, Belgium

GABA and its type A receptor (GABA_AR) are present in the immature CNS and may function as growth-regulatory signals during the development of embryonic neural precursor cells. In the present study, on the basis of their isopycnic properties in a buoyant density gradient, we developed an isolation procedure that allowed us to purify proliferative neural precursor cells from early postnatal rat striatum, which expressed the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). These postnatal striatal PSA-NCAM⁺ cells were shown to proliferate in the presence of epidermal growth factor (EGF) and formed spheres that preferentially generated neurons in vitro. We demonstrated that PSA-NCAM⁺ neuronal precursors from postnatal striatum expressed GABA_AR subunits in vitro and in situ. GABA elicited chloride currents in PSA-NCAM⁺ cells by activation of functional GABA_AR that displayed a typical pharmacological profile. GABA_AR activation in PSA-NCAM⁺ cells triggered a complex intracellular signaling combining a tonic inhibition of the mitogen-activated protein kinase cascade and an increase of intracellular calcium concentration by opening of voltage-gated calcium channels. We observed that the activation of GABA_AR in PSA-NCAM⁺ neuronal precursors from postnatal striatum inhibited cell cycle progression both in neurospheres and in organotypic slices. Furthermore, postnatal PSA-NCAM⁺ striatal cells synthesized and released GABA, thus creating an autocrine/paracrine mechanism that controls their proliferation. We showed that EGF modulated this autocrine/paracrine loop by decreasing GABA production in PSA-NCAM⁺ cells. This demonstration of GABA synthesis and GABA_AR function in striatal PSA-NCAM⁺ cells may shed new light on the understanding of key extrinsic cues that regulate the developmental potential of postnatal neuronal precursors in the CNS.

Key words: GABA_A receptors; newborn rat striata; proliferation; PSA-NCAM; whole-cell patch-clamp; RT-PCR; HPLC; immunocytochemistry

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^* S.B. and J.-M.R. contributed equally to this work.

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2383278-17$05.00/0

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