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Page 240 Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02

In rodent models of neurogenesis, radial glia-like NSCs located in the SGZ give rise to NPCs [102] . The
neurogenic process involves five intricate stages, ultimately leading to the integration of newly mature
granule cells in the hippocampus. During the first stage, NSCs proliferate and generate neural progenitors
in the SGZ. Stage 2 is the continuous phase of survival, where NSC and progenitor cells are lost through
apoptosis, in this early part of the process. During stage 3, progenitor cells undergo fate determination
and differentiate into immature neurons. In stage 4, immature neurons migrate a short distance within
the granule cell layer where they continue their maturation and integrate (Stage 5) into the hippocampal
circuitry, receiving input from the entorhinal cortex, and projecting axons to the CA3 (mossy fibers) and
hilar regions of the hippocampus [101,103-106] , which further synapse with CA1 pyramidal cells [107] .

In epilepsy, while the stimuli to trigger adult neurogenesis are activated, the orchestrated differentiation
process is dysregulated at various steps. The newly formed granule neurons do not integrate appropriately
into the dentate gyrus, thus forming aberrant connections with other neuronal cells, and contributes
to epilepsy and associated cognitive decline [108-110] .

The role of microglia in physiological neurogenesis
Variations in neurogenesis properties from the embryonic stages to adulthood have been studied and
show that newborn neuron populations decrease with age [111] , potentially due to a lowered ability of
NSCs to regenerate [112] , or changes in environmental cues in the hippocampus, including an activated
state of microglia [113] . Microglia have been shown to participate in neurogenesis, during multiple stages
of the process through the contribution of factors that affect the proliferation and survival of NSCs [114,115] .
Cognitive decline has been correlated with decreased neurogenesis [116] , and studies provide support to
the idea that exercise or enriched environments result in an increase in neurogenesis [117-119] , which may
be modulated by microglial activation [120] . A pro-inflammatory environment has been demonstrated to
inhibit adult neurogenesis, while anti-inflammatory treatments were able to rescue the phenotype [121,122] .
All these findings demonstrate the need to understand the role of microglia in neurogenesis that takes
place in the physiological and pathological CNS. The function of microglia is most likely influenced by the
environmental signals in a particular setting, which will dictate the direction of their activation status.

Microglia constantly survey their environment and are in the proximity of all cell types during neurogenesis,
including newborn neurons. They are also involved in the phagocytosis of NPCs and neuroblasts in a
[51]
homeostatic role for maintaining neurogenic stem cells without releasing pro-inflammatory cytokines .
In concordance with these data, ablating microglia in the DG inhibited adult neurogenesis by diminishing
neuroblast survival [123] . Although these effects are most likely mediated by the secretion of cytokines and
by microglial-regulated phagocytosis, the influence of microglia on neurogenesis also extends beyond
these molecular steps and events. There is a growing body of evidence demonstrating that microglial
receptors can modulate their activity in neurogenesis. For example, microglial P2Y13 receptor was
recently described to contribute to microglial structural integrity. When the P2Y13 receptor is knocked
out, increases in proliferation of NPCs and new neurons are observed, and this may be another way
to regulate neurogenesis [124] . CX3CR1 has also been demonstrated to be involved in the regulation of
adult neurogenesis: microglia have been reported to activate NPCs through CX3CR1 pathways in the
hippocampus [125] , and CX3CR1 null (-/-) mice exhibited impaired connectivity and aberrant synapse
formation [126] . This was further supported by genetic and pharmacological inhibition of CX3CR1 signaling,
which also led to aberrant neurogenesis [127,128] .

Abundant data show that microglia are critical in adult neurogenesis and regulate several stages of accurate
incorporation of new neurons into the hippocampal circuitry. As several seizure disorders and models
manifest predominantly in the hippocampus, the effects of epileptic activity on SGZ neurogenesis is
starting to be uncovered.