Apoptosis of Glutamatergic Neurons Fails to Trigger a Neurogenic Response in the Adult Neocortex

Abstract

Adult neurogenesis is actively studied in part because of the potential to manipulate endogenous neural stem and progenitor cells for tissue repair. Although constitutive generation of neurons in the adult rodent olfactory bulb and hippocampal dentate gyrus is widely accepted and stroke-induced generation of striatal inhibitory neurons consistently observed, evidence supporting the generation of neurons in the neocortex after neuronal loss remains slim. Nevertheless, a few studies suggested that targeted apoptosis of neocortical glutamatergic neurons could trigger the generation of new ones in the adult brain. In light of such studies, we tested whether apoptosis of glutamatergic cortical neurons using two novel transgenic approaches in mice, an inducible Caspase-8 protein and an inducible diphtheria toxin gene, results in new neurons. After a thorough analysis, no new neurons were detected in the neocortex. Interestingly, an increase in the expression of the neuroblast marker DCX was observed in both models, in some cases in cells with morphologies previously associated with poststroke neuroblasts, but DCX ϩ cells coexpressed the oligodendrocyte precursor marker Olig2, suggesting caution when using DCX as a marker for neuroblasts after injury. Given that the adult neocortex lacks an innate potential to regenerate lost glutamatergic neurons, future strategies should concentrate on manipulating the differentiation potential of endogenous or exogenous precursor cells.

Apoptotic neurons induce proliferative responses of progenitor cells in the postnatal neocortex

“…Consistent with previous report (Diaz et al, 2013), we observed that microglial reactions represent the earliest cellular response to DT-triggered apoptotic cell death.…”

“…This hypothesis has not been confirmed in other studies (Arvidsson et al, 2002;Shimada et al, 2010;Diaz et al, 2013). To address this issue, we labeled progenitor cells in SVZ at P3 by intraventricular injection of lentiviruses carrying GFP-expressing construct (Figs.…”

Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain

“…No clear evidence of spontaneous neurogenesis has been shown in the intact mouse (as opposed to rat) cerebral cortex, thus confirming the importance of the animal species in parenchymal neurogenesis (see Table 1) and the possible differences existing in cortical structural plasticity when comparing rats and mice. On the other hand, striking results have been obtained in the lesioned mouse cortex (Magavi et al 2000;Chen et al 2004), but this remains controversial and awaits validation (Diaz et al 2013).…”

Adult neural stem cells: plastic or restricted neuronal fates?

“…However, this generation of new neurons in the postnatal/adult cortex seems to be dependent on unknown signals: those not usually elicited by most types of lesions (Saha et al, 2012;Diaz et al, 2013). It is also still unclear whether these new neurons could be derived from progenitor cells in the parenchyma itself (Palmer et al, 1999;Guo et al, 2010) or the marginal zone/layer 1 (Costa et al, 2007;Ohira et al, 2010).…”