title: 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.
abstract: GABA and its type A receptor (GABA(A)R) 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(A)R subunits in vitro and in situ. GABA elicited chloride currents in PSA-NCAM+ cells by activation of functional GABA(A)R that displayed a typical pharmacological profile. GABA(A)R 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(A)R 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(A)R 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.
authors.affiliation: Center for Cellular and Molecular Neurobiology, University of Liège, B-4020 Liège, Belgium. laurent.nguyen@student.ulg.ac.be
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Malgrange
authors.forename: Ingrid
authors.initials: I
authors.lastname: Breuskin
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
authors.forename: Gustave
authors.initials: G
authors.lastname: Moonen
authors.forename: Shibeshih
authors.initials: S
authors.lastname: Belachew
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rigo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002469:Cell Separation; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis*; D009474:Neurons / Q000166:cytology; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012794:Sialic Acids / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018874:Spheroids, Cellular; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D007527:Isoenzymes; D039842:Neural Cell Adhesion Molecule L1; D011963:Receptors, GABA-A; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule; D005680:gamma-Aminobutyric Acid; D004815:Epidermal Growth Factor; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D002118:Calcium