NMDA modulates oligodendrocyte differentiation of subventricular zone cells through PKC activation

Fabio Cavaliere,Carlos Matute,Mitradas Panicker,Monica Benito-Muñoz

doi:10.3389/fncel.2013.00261

Abstract

Multipotent cells from the juvenile subventricular zone (SVZ) possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes, or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX) as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.

Highlights

Extracellular glutamate is one of the most important neurotransmitters and neuromodulators of the CNS
Our previous results demonstrated that overstimulation of NMDA receptors of subventricular zone (SVZ) multipotent cells induced an increase of oligodendrocyte differentiation through NADPH oxidase (NOX)-dependent generation of ROS (Cavaliere et al, 2012)
To confirm the involvement of PKC in NMDA mediated oligodendrocyte differentiation we counted the number of MBP+

Summary

Introduction

Extracellular glutamate is one of the most important neurotransmitters and neuromodulators of the CNS. It participates in different functions such as synaptic plasticity, LTP and learning, glia-neuron communication, or transduction of sensory input at the periphery and nociceptive pathway (for a review, see Fellin and Carmignoto, 2004; Carozzi et al, 2008; Niswender and Conn, 2010). Depending on their molecular structure and pharmacology, they can be divided in AMPA (GluA1–GluA4), kainate (GluK1– GluK5), NMDA (GluN1, GluN2A–GluN2D, GluN3A-B) receptor subtypes. NMDA receptor activation requires the co-activation of glycine (Kleckner and Dingledine, 1988), and the receptors bearing GluN3 subunits bear more affinity for this amino acid (Yao and Mayer, 2006)

Methods

Results

Discussion

Conclusion