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The Journal of Neuroscience, November 17, 2004, 24(46):10343-10352; doi:10.1523/JNEUROSCI.3229-04.2004

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Development/Plasticity/Repair
PHCCC, a Specific Enhancer of Type 4 Metabotropic Glutamate Receptors, Reduces Proliferation and Promotes Differentiation of Cerebellar Granule Cell Neuroprecursors

A. M. Canudas,¹ V. Di Giorgi-Gerevini,¹ L. Iacovelli,^1,3 G. Nano,¹ M. D'Onofrio,³ A. Arcella,³ F. Giangaspero,² C. Busceti,³ L. Ricci-Vitiani,⁴ G. Battaglia,³ F. Nicoletti,^1,3 and D. Melchiorri¹

Departments of ¹Human Physiology and Pharmacology and ²Experimental Medicine, University of Rome La Sapienza, 00185 Rome, Italy, ³Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, and ⁴Department of Hematology, Istituto Superiore di Sanità, 00185 Rome, Italy

Exposure of immature rat cerebellar granule cell cultures to the type 4 metabotropic glutamate (mGlu4) receptor enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) reduced [³H]thymidine incorporation. Its action was sensitive to the growth conditions and was attenuated by two mGlu4 receptor antagonists. An antiproliferative action of PHCCC was also seen in cultures from wild-type, but not mGlu4, knock-out mice. At least in rat cultures, PHCCC was not neurotoxic and enhanced neuritogenesis. Although PHCCC reduced the increase in cAMP formation and phospho-AKT levels induced by forskolin, none of these transduction pathways significantly contributed to the reduction of [³H]thymidine incorporation. Interestingly, PHCCC reduced the expression of Gli-1, a transcription factor that mediates the mitogenic action of Sonic hedgehog. Finally, we treated newborn rats with PHCCC either intracerebrally (infusion of 5 nmol/2 µl in the cerebellar region once every other day) or systemically (5 mg/kg, i.p., once daily) from postnatal days 3-9. Local infusion of PHCCC induced substantial changes in the morphology of the developing cerebellum. In contrast, systemic injection of PHCCC induced only morphological abnormalities of the cerebellar lobule V, which became visible 11 d after the end of the treatment. These data suggest that mGlu4 receptors are involved in the regulation of cerebellar development.

Key words: type 4 metabotropic glutamate receptor; PHCCC; cerebellar granule cell neuroprecursors; proliferation; differentiation; development

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Received April 7, 2004; revised September 16, 2004; accepted September 20, 2004.

This article has been cited by other articles:

				L. Iacovelli, A. Arcella, G. Battaglia, S. Pazzaglia, E. Aronica, P. Spinsanti, A. Caruso, E. De Smaele, A. Saran, A. Gulino, et al. Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Inhibits the Growth of Medulloblastomas. J. Neurosci., August 9, 2006; 26(32): 8388 - 8397. [Abstract] [Full Text] [PDF]

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