Abstract
New neurons are continuously generated in two adult brain regions: the subgranular zone of the hippocampus and the subependyma by the lateral ventricles, referred to as the neurogenic niches. During their development from neural stem cells to mature functionally integrated neurons numerous choices are made, such as proliferation or quiescence, cell survival or death, migration or establishment, growth or retraction of processes, synaptic assembly or pruning, or tuning of synaptic transmission. The process is altered by physiological stimuli as well as several brain diseases. Microglia are located within the neurogenic niches and have become interesting candidates for modulating neurogenesis in both the healthy and injured brain. They become activated by foreign antigens or changes in the brain homeostasis and transform this innate immunity into an adaptive immune response by recruiting systemic immune cells. Most studies report an acute decrease in the survival of new neurons following this classically activated microglia reaction. The long-term effects are more complex. In neurodegenerative diseases, microglial activation is more heterogeneous and the transformation from a pro- to an anti-inflammatory cytokine profile and the deactivation of microglia is not well defined. The diversity is reflected by numerous reports describing both beneficial and detrimental effects on neurogenesis, primarily on the proliferation, survival, and cell fate. However, relatively few studies have investigated alterations at later stages of neurogenesis including the functional integration. Though likely, it is not established how a fine-tuned cross-talk between microglia and adult-born neurons would work and how it changes upon microglia activation. This review will therefore launch three hypotheses for how microglia might direct synaptic integration of newborn neurons, currently a fast expanding research field.
Highlights
New neurons are continuously generated in two adult brain regions: the subgranular zone of the hippocampus and the subependyma by the lateral ventricles, referred to as the neurogenic niches
They act as neural stem cells/precursors (Riquelme et al, 2008), (2) ependymal cells by the subependymal layer that regulate the absorption of ions, transport factors from the cerebral spinal fluid into the parenchyma, and act as a source of secreted pro-neurogenic factors like transforming growth factor (TGF)-α and basic fibroblast growth factor (Riquelme et al, 2008), (3) blood vessels that undergo a parallel angiogenesis within the niche and often use common factors with neurogenesis such as vascular endothelial growth factor, nitric oxide and erythropoietin (Riquelme et al, 2008), (4) meningeal projections, extracellular matrix (ECM) proteins, basal lamina, and perivascular cells and fibroblasts, which propagate or modulate signals from the blood vessels and cerebral spinal fluid as well as from surrounding brain parenchyma
Cell adhesion to its environment includes matrix components, extracellular proteolytic enzymes, integrins, and non-receptor tyrosine kinases, which influence both gene expression and post-transcriptional signaling cascades (Riquelme et al, 2008; Wojcik-Stanaszek et al, 2011), (5) interneurons and other neighboring mature neurons already highly integrated into the hippocampal network, which may modulate neurogenesis by activity- and signaling-dependent mechanisms (Markwardt et al, 2011; Masiulis et al, 2011; Toni and Sultan, 2011), (6) oligodendrocytes, which are numerous in the subependyma but few in the subgranular zone (SGZ)
Summary
New neurons are continuously generated in two adult brain regions: the subgranular zone of the hippocampus and the subependyma by the lateral ventricles, referred to as the neurogenic niches. FROM NEURAL STEM CELLS TO MATURE FUNCTIONALLY INTEGRATED NEURONS – CHOICES TO BE MADE Neurogenesis persists in two adult brain regions: the subependyma of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus.
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