Characterization of the Neurogenic Response to Apoptosis of Cortical Glutamatergic Neurons in the Adult Brain

Abstract

During the last twenty years much has been learned about genes involved in the proliferation, migration and differentiation of neural stem and progenitor cells (NSPCs) in the two main adult neurogenic niches: the ventricular/subventricular zone (VZ/SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. In addition, many are addressing the function of new neurons in those two regions. However, a third aspect with incredible translational potential, whether endogenous NSPCs are capable of replacing glutamatergic neocortical neurons after injury or disease, has not been thoroughly and convincingly addressed. Here to test and answer that question, two noninvasive models of glutamatergic neuronal apoptosis were generated and characterized: inducible neuron specific diphtheria toxin or CamkCreER-DTA and inducible neuron specific Caspase8 or Camk-iCaspas8. However, after a thorough analysis no newborn neurons or bromodeoxyuridine/NeuN (BrdU/NeuN) co-labeled cells were detected in the neocortex of either model. Although neuron specific apoptosis lead to gliosis and microglia activation, neurogenesis in the two main adult neurogenic niches, the VZ-SVZ and subgranular zone (SGZ) of the hippocampus, was unaffected.;Doublecourtin (DCX) expression was noticeably upregulated in areas of extensive cell death but most to all of those cells expressed the oligodendrocyte precursor marker Olig2. These results suggest that adult neural stem and progenitor cells are incapable of replacing lost glutamatergic neurons and caution against using DCX solely as a marker of neurogenesis in areas of extensive neuronal death.