Excitement keeps your brain cells alive María E. Fernández and Olivier Raineteau* Brain Research Institute, University of Zurich/ETHZ, Zurich, Switzerland *Correspondence: raineteau@hifo.uzh.ch A commentary on NMDA receptors activated by subventricu- lar zone astrocytic glutamate are critical for neuroblast survival prior to entering a syn- aptic network. by Jean-Claude Platel, Kathleen A. Dave, Valerie Gordon, Benjamin Lacar, Maria E. Rubio, and Angélique Bordey (2010). Neuron 65, 859–872. One of the most dynamic features of the postnatal and adult mammalian brain is certainly the continuous cellular replace- ment taking place in discrete regions of the forebrain. In rodents, the subventricu- lar zone (SVZ) of the lateral ventricles produces 10,000–30,000 neuroblasts daily (Lois and Alvarez-Buylla, 1994), which will migrate and eventually form functional connections within the olfactory bulb (OB) neuronal circuitry. This unique process is characterized by its extreme complexity, with distinct stages of differentiation controlled in a tight spa- tiotemporal manner. Neural stem cells (also called neurogenic astrocytes) reside in the walls of the lateral ventricles, where after a transient amplification phase, they generate committed neuroblasts. These neuroblasts migrate great distances via the rostral migra- tory stream (RMS) to the OB, a journey tak- ing several days. In the olfactory bulb they invade different layers into which they func- tionally integrate, participating in olfactory processing (see for example, Mouret et al., 2009). This fascinating multistep process needs to be precisely controlled, optimiz- ing the number of newly generated neurons necessary to adapt to a changing olfactory environment (Alonso et al., 2006). Increasing evidence reveals a central role for neurotransmitters in precisely regulating several key steps of the neurogenic process. In the SVZ, asynaptic release of GABA or glutamate by the neuroblasts and SVZ astro- cytes, respectively, antagonistically influence proliferation and therefore ultimately the www.frontiersin.org size of the newly generated neuroblast pool (reviewed in Platel et al., 2008). Glutamate can bind to different types of receptors. Neuroblasts express one or several of the metabotropic (mGluR5) and ionotropic glutamate receptors (i.e., AMPA, Kainate; reviewed in Platel et al., 2010a), and grad- ually acquire NMDA receptors while they migrate, as discussed below. These receptors carry out different functions. Neuroblast migration is affected by Kainate receptor blockade (GluK2). In contrast, activation of metabotropic glutamate receptor (mGluR5) has no effect on neuroblast migration but their blockade result in a marked reduction of the number of proliferative cells in the SVZ (Melchiorri et al., 2007). Another level of regulation occurs in the OB, where local activity affects the survival of newborn neu- rons whilst they synaptically integrate into the OB neuronal circuitry (Alonso et al., 2006; Mouret et al., 2009). Recent work by Platel et al. (2010b) identifies a new role for the glutamate NMDA receptors (NMDARs) in promot- ing the survival of migrating neuroblasts through their protracted journeys towards the OB. By performing perforated patch- clamp recording at defined rostro-caudal levels of the RMS combined with calcium imaging, the authors have demonstrated a gradual expression of functional NMDARs in migrating neuroblasts, which are spon- taneously activated resulting in transient intracellular calcium increases. They next used an elegant method of electroporation of a Cre-expressing plasmid in the SVZ of Rosa26STOP-YFP neonatal mice, resulting in the conditional but permanent labeling of cohorts of newly generated neuroblasts. This method, when applied in NR1floxed/ Rosa26STOP-YFP mice, resulted in single cell knockouts (KOs) for the NMDAR, leading to a significant decrease in the number of neuroblasts reaching the OB. Immunodetection of activated caspase-3 revealed a parallel increase in the number of apoptotic neuroblasts in the RMS, an effect also observed after in vivo blockade Glarne Cyra tnemo published: 24 June 2010 doi: 10.3389/fnins.2010.00046 of NMDARs. Thus, blocking NMDAR activity by different means increases apop- tosis of migrating neuroblasts that results, over time, in a cumulative decrease of OB granule cell neurogenesis (65% at 8 weeks post-electroporation). Importantly, the migration of the electroporated neuroblasts was not influenced by genetic removal of NMDARs indicating that apoptosis alone contributes to defective neurogenesis. Interestingly, although NMDARs might play a role in the successful synaptic inte- gration of newborn neurons in the OB circuitries, the initial phase of neuroblast apoptosis occurs in the rostral SVZ and RMS, two asynaptic environments. Platel et al., provide detailed analyses of the cell types and mechanisms involved in the asynaptic glutamate release resulting in the activation of NMDARs on migrating neuroblasts. By combining immunostain- ing for l-glutamate as well as for the vesic- ular glutamate transporter VGlut1 with astrocytic and neuroblasts markers (Glast and DCX, respectively), they show at the microscopic and ultrastructural level, that within the RMS, only astrocytes express glutamate and the machinery for its vesicu- lar release. Furthermore, a calcium increase in RMS astrocytes induced NMDAR acti- vation in migrating neuroblasts. This was notably shown in acute sagittal forebrain slices prepared from transgenic mice that express the Gq-coupled receptor MrgA1 exclusively in astrocytes, in which a cal- cium increase can be evoked by using an agonist (FLRF) that does not bind to endogenous receptors in the brain (Fiacco et al., 2007). Altering astrocytic vesicular release by using the Clostridium botulinum neurotoxin BoNT/B significantly reduced NMDAR activity in neuroblasts, an effect not observed with the neuronal specific neurotoxin BoNT/A. Taken together, these results reveal a previously unsuspected role for NMDARs in modulating the survival of neuroblasts migrating within an asynaptic environ- ment. Together with previous work from June 2010 | Volume 4 | Article 46 | 1