Glutamate and Regulation of Proliferation in the Developing Mammalian Telencephalon

Abstract

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.

Expression of the eight AMPA receptor subunit genes in the developing central nervous system and sensory organs of zebrafish

“…However, neuronal differentiation in the olfactory bulb occurs during the second day of development (Sakata et al, 2003). This taken together with our findings of an early expression of AMPARs suggests that they play similar roles in the proliferation and migration of forebrain progenitors as described for mammals (Luk and Sadikot, 2004;Manent et al, 2006).…”

“…An appropriate level of AMPA receptor activation was shown to be crucial for cell survival of early cortical neurons (Drian et al, 2001). Furthermore, AMPA receptor (AMPAR) function was shown to be involved in developmental processes including retraction and elongation of glial processes (Ishiuchi et al, 2001), proliferation of cortical progenitors (Luk and Sadikot, 2004), and the proliferation and differentiation of retinal progenitors (Martins et al, 2006). These findings suggest that AMPAR signaling and the regulation of their expression may play an important role not only in the function, but also in the development of the nervous system.…”

AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate

“…In rodents, functional GluAs are expressed in proliferative neural precursor cells in addition to mature neurons (60,61). However, prior in vitro studies have not identified which cells expressing GluAs are required for progenitor differentiation (11,12). In the present study, we demonstrated that GluAs are crucial for the development of GluA-expressing cells, as shown by the partial arrestin expression and arrested axonal extension of GluAexpressing cells in promoter-induced ci-R electroporated larvae (Fig.…”

“…For example, mouse gluA transcripts are detectable by embryonic day 10, and in zebrafish, zygotic gluA transcripts are expressed as early as the midblastula stage (4-10). These observations, combined with in vitro results, suggest a role for GluAs in neural cell proliferation (11,12). In vertebrates, GluAs form tetramers consisting of various combinations of four subunits (GluA1-GluA4) (13)(14)(15).…”

Neuregulin1/ErbB4-induced migration in ST14A striatal progenitors: calcium-dependent mechanisms and modulation by NMDA receptor activation

“…NMDA at high concentrations can be cytotoxic, depending on receptor density and subunit composition [27]. NMDA could also increase cell proliferation and/or survival, as demonstrated by several groups by in vivo and in vitro experiments [28,29]. …”