The use of neural progenitor cells (NPCs) is limited by the incomplete knowledge of the extracellular signals regulating their proliferation and survival. We report that cultured mouse NPCs express functional mGlu3 and mGlu5 metabotropic glutamate receptors. Pharmacological blockade of both receptors reduced NPC proliferation and survival, whereas activation of mGlu5 receptors substantially enhanced cell proliferation. Adult mice lacking mGlu5 receptors or treated with mGlu5 or mGlu3 receptor antagonists showed a dramatic reduction in the number of dividing neuroprogenitors present in the subventricular zone and in the dentate gyrus of the hippocampus. These data disclose a novel function of mGlu receptors and offer new potential strategies for the optimization of cell replacement therapy in neurodegenerative disorders.

Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNAalkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-jB pathway that supports the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNAalkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

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Neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of postnatal mice, and cultured as neurospheres, expressed functional mGlu3 receptors. Following mitogen withdrawal and plating onto poly-ornitine-coated dishes, cells dissociated from the neurospheres differentiated into GFAP(+) astrocytes (about 85%), and a small percentage of beta-III tubulin(+)-neurons and O1(+)-oligodendrocytes. Activation of mGlu3 receptors with LY379268 (100 nM, applied every other day), during the differentiation period, impaired astrocyte differentiation, favoring the maintenance in culture of proliferating progenitors co-expressing GFAP with the immature markers, Sox1 and nestin. Co-treatment with the preferential mGlu2/3 receptor antagonist, LY341495 (100 nM), reversed this effect. We examined whether mGlu3 receptors could modulate the canonical signaling pathway activated by bone morphogenic proteins (BMPs), which are known to promote astrocyte differentiation of SVZ/NSCs. An acute challenge of cells isolated from the neurospheres with BMP4 (100 ng/mL) led to phosphorylation and nuclear translocation of the transcription factors, Smads. This effect was largely attenuated by the mGlu2/3 receptor agonist, LY379268. The interaction of mGlu3 and BMP4 receptors was mediated by the activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, LY379268 failed to affect BMP receptor signaling when combined with the MAPK kinase inhibitor, UO-126 (30 muM). These data raise the intriguing possibility that glutamate regulates differentiation of SVZ/NSCs by activating mGlu3 receptors.