Glutamate and regulation of proliferation in the developing mammalian telencephalon

Increasing evidence suggests that classical neurotransmitters play an important morphogenetic role during development of the mammalian central nervous system. Using in vitro and in vivo models, we have previously identified a role for the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors in the proliferation of striatal progenitors. Here, we compare the roles of ionotropic glutamate receptors in the proliferation of either striatal or cortical progenitors. In culture, glutamate receptor activation promoted proliferation of both striatal and cortical neuroblasts. However, cortical and striatal neuroblasts responded to distinct ionotropic receptors. Cortical cultures were sensitive to AMPA/KA receptor blockade, whereas striatal neuroblast proliferation was altered by NMDA antagonists. In vivo, BrdU uptake in the proliferative ventricular zone was reduced in embryos following acute administration of ionotropic glutamate receptor antagonists. In keeping with in vitro observations, proliferation in cortical and striatal ventricular regions was reduced, respectively, by either AMPA/KA or NMDA receptor blockade. We also determined whether forebrain-derived progenitors expanded as neurospheres in the presence of growth factors show similar ionotropic glutamatergic responses. Cells in neither dorsal nor ventral telencephalon-derived neurospheres showed altered proliferation following exposure to either class of ionotropic glutamate receptor antagonist. Together, these findings suggest that glutamate influences the proliferation of forebrain neuronal progenitors, but not more primitive populations represented in multipotential progenitors expanded in vitro. The effects on neuroblast proliferation in different forebrain domains are heterogeneous and are mediated by distinct subclasses of ionotropic glutamate receptors.