The Journal of Neuroscience, April 15, 2003, 23(8):3278
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
Laurent
Nguyen1,
Brigitte
Malgrange1,
Ingrid
Breuskin1,
Lucien
Bettendorff1,
Gustave
Moonen1, 2,
Shibeshih
Belachew1, 2, *, and
Jean-Michel
Rigo1, *
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 (GABAAR)
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 GABAAR subunits in
vitro and in situ. GABA elicited chloride
currents in PSA-NCAM+ cells by activation of
functional GABAAR that displayed a typical pharmacological
profile. GABAAR 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
GABAAR 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 GABAAR 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:
GABAA receptors; newborn rat striata; proliferation; PSA-NCAM; whole-cell patch-clamp; RT-PCR; HPLC; immunocytochemistry
*
S.B. and J.-M.R. contributed equally to this work.
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