mGLU3 metabotropic glutamate receptors modulate the differentiation of SVZ‐derived neural stem cells towards the astrocytic lineage

Abstract

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.

Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine

“…We are aware of the interpretative limitations of data generated by single mGlu ligands, as the distinct functions of mGlu2 and mGlu3 are not fully understood. For this reason, even if we did not observe significant effects of ALC on mGlu3 protein levels, at present we cannot exclude that this receptor subtype, which has been shown to be functionally expressed by adult NPC (Di Giorgi-Gerevini et al, 2005;Ciceroni et al, 2010), may also be involved. We also proved that chronic ALC reverted depressive-like behavior in a predictive animal model.…”

Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

“…This mechanism cannot be applied here because we have eliminated the endogenous excitotoxic component from A␤ neurotoxicity with a cocktail of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate re- ceptor antagonists (see above). In cultured neural stem cells, mGlu3 receptors negatively regulate the activity of bone morphogenetic protein receptors, which share the same transduction mechanisms of TGF-␤ receptors (Ciceroni et al, 2010). It will be interesting to examine whether neuronal mGlu2 receptors functionally interact with receptors that support neuronal survival, such as TGF-␤ receptors.…”

Neuron–glia signaling: Implications for astrocyte differentiation and synapse formation

“…Pharmacological activation of mGlu3 receptors inhibits the astrocytic differentiation of neural stem cells isolated from the SVZ by negatively modulating BMP receptor signaling (Ciceroni et al, 2010). We also demonstrated that mGlu2/3 receptor activation by neurons induces TGF-β1 secretion, leading to GFAP gene activation and astrocyte differentiation (Romão et al, 2008).…”