The role of glutamate and its receptors in the proliferation, migration, differentiation and survival of neural progenitor cells

Abstract

The mammalian central nervous system derives from multipotent neural progenitor cells (NPCs) of the developing brain. During development the progenitor cells have enormous potential. They proliferate actively and differentiate into all the three main cell types, i.e., neurons, astrocytes and oligodendrocytes, of the adult brain through a tightly regulated process that coordinates cell proliferation, survival, migration, differentiation and apoptosis. This process is regulated by multiple extracellular signals including neurotrophic factors, chemoattractants and neurotransmitters in a coordinated manner. The main excitatory neurotransmitter glutamate is involved in promoting and/or inhibiting the proliferation, survival, migration and differentiation of NPCs acting via ionotropic or metabotropic receptors. The role of glutamate in the regulation of cortical NPCs has been most extensively studied. Glutamate appears to have a similar role in hippocampal, striatal as well as adult neural progenitors. Ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors and metabotropic glutamate receptor 5 (mGluR5) are expressed early during embryonic development as well as in the neurogenic zones of the adult brain. Ca(2+)-permeable AMPA/KA receptors are initially of importance for cell proliferation and neuronal motility. At later stages of development N-methyl-D-aspartate (NMDA) receptors have a more prominent role. MGluR5, which is the main metabotropic glutamate receptor during early development, is expressed in early progenitors and radial glial cells. Activation of this receptor promotes the proliferation and survival of NPCs. MGluR5 is involved in the extension of radial glial processes and in regulation of the migration of early cortical neurons.

Myelin Proteolipid Protein Complexes with v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

“…This is likely a protective effect as prolonged Ca 2ϩ influx would be cytotoxic to OPCs and result in cell death (Itoh et al, 2002;Deng et al, 2006).…”

“…One might predict, based on studies on neurons, that AMPA receptors lacking GluR2 would be more permeable to Ca 2ϩ (Iihara et al, 2001), so that after AMPA stimulation, there would be an increase in Ca 2ϩ signaling and perhaps an increase in OPC migration in GluR2 Ϫ/Ϫ OPCs. Unexpectedly, however, the numbers of Ca 2ϩ transients in GluR2 Ϫ/Ϫ OPCs were reduced at baseline, indicating that these cells had reduced Ca 2ϩ signaling even in the absence of AMPA.…”

“…The responsiveness of OPCs to glutamate may regulate the degree of this pathology. During oligodendrocyte lineage progression, cells alter the subunit composition of their AMPA receptors, which in turn alters their Ca 2ϩ conductance (Itoh et al, 2002;Brand-Schieber and Werner, 2003;Deng et al, 2006). Thus, OPCs and mature oligodendrocytes are differentially susceptible to high levels of glutamate.…”

“…All animal procedures were approved by the University of Colorado Institutional Animal Care and Use Committee or the Institutional Animal Care and Use Committee of the Cleveland Clinic Foundation. Mouse lines used were PLP null mice (Pende et al, 1994;Klugmann et al, 1997;Yuan et al, 1998;Deng et al, 2003Deng et al, , 2004Káradó ttir et al, 2005;Salter and Fern, 2005;Narayanan et al, 2009), GluR2null mice (Iihara et al, 2001;Narayanan et al, 2009;Tyler et al, 2009;Wahl et al, 2014), and ␣v integrin heterozygous mice (Bader et al, 1998;Fyffe-Maricich et al, 2011Ishii et al, 2012). All lines were crossed with PLP-EGFP mice (Barres et al, 1994;Ahlgren et al, 1997;Mallon et al, 2002;Huang et al, 2011), in which the Plp1 promoter drives EGFP in cells of the oligodendroglial lineage.…”

“…؊/؊ and ␣v integrin ؉/؊ OPCs did not increase migration in response to AMPA To examine the roles of the GluR2 AMPA receptor subunit and ␣v integrin in neurotransmitter-mediated OPC migration, we crossed the PLP-EGFP line with GluR2 null (Iihara et al, 2001) or ␣v integrin heterozygous mice (Bader et al, 1998). These studies had to be done with ␣v integrin heterozygous mice because the majority of ␣v integrin null mice die in utero (Bader et al, 1998) and we were unable to obtain postnatal ␣v integrin null mice.…”