Excitement Keeps Your Brain Cells Alive

of NMDARs. Thus, blocking NMDAR activity by different means increases apoptosis 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 integration 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 immunostaining for l-glutamate as well as for the vesicular 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 vesicular release. Furthermore, a calcium increase in RMS astrocytes induced NMDAR activation 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 calcium 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 environment. Together with previous work from 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 gradually 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 neurons 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 promoting the survival of migrating neuroblasts through their protracted journeys towards the OB. By performing perforated patchclamp 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 spontaneously activated resulting in transient intracellular calcium increases. They next used an elegant method of electroporation of a Cre-expressing plasmid in the SVZ of Rosa26 neonatal mice, resulting in the conditional but permanent labeling of cohorts of newly generated neuroblasts. This method, when applied in NR1/ Rosa26 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 A commentary on