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Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02 Page 239
[77]
involved in the organization of synapses . Like IL-1β, TNF-α also affects GABA levels by increasing
[78]
GABA receptor endocytosis, reducing its inhibitory action . Another pro-inflammatory cytokine, IL-6,
is upregulated by TNF-α and IL-1β. IL-6 has been reported to decrease hippocampal neurogenesis while
[79]
increasing microgliosis, possibly contributing to epileptogenesis .
Changes in microglia post-seizure
The question of microglial activation status and its effects post-seizure have yet to be answered. Microglia
modulate the severity of early seizures in a pilocarpine model with lipopolysaccharide (LPS) pre-
[80]
conditioning : ablation of microglia prior to seizure onset resulted in dramatic increases of seizure
severity. Since no other cell types were affected by the method of microglia ablation [81,82] , it is suggested
that microglia may play a role early on in seizure induction to protect the CNS from exaggerated neuronal
activity. The presence of microglia may thus be beneficial during seizure; however, evidence suggests
that their activation may be detrimental post-seizure. Minocycline, a tetracyclic antibiotic that has anti-
inflammatory properties, has been shown to act as an inhibitor of microglial proliferation/activation .
[83]
Studies that used minocycline have reported that it protects against neuronal cell death after seizures, thus
[84]
indicating that microglia contribute to neurodegeneration following seizures . Other studies demonstrated
that a 2-week course of minocycline post-status epilepticus decreased the number, duration, and severity
of spontaneous recurrent seizures, suggesting that microglia are involved in the propagation of these SRS [85-
87] . It should also be noted, on the other hand, that there are studies that show only partial effectiveness by
minocycline , or inability to reverse the increase of epileptogenesis [89,90] .
[88]
[91]
Inflammatory cytokines increase neuronal excitability and are believed to contribute to epileptogenesis .
Though inflammatory cytokines are expressed by several cell types in the brain, microglia-specific pro-
inflammatory cytokines, such as IL-1β, IL6 and TNF-α, showed increased expression three days after SE
[63]
but had diminished by day 21 . Levels of anti-inflammatory cytokines, such as Arg1, IL-4 and IL-10,
were also increased. These data contribute to the existing controversy on the role that microglia and
cytokines play post-seizure. Additionally, Toll-like receptor (TLR) signaling has been implicated in the
production of cytokines in seizure models. Studies have demonstrated that the downregulation of TLR3
and TLR4 activities reduces recurrent and acute seizures, respectively [92,93] . Another study showed that the
activated TLR4 pathway (mediated by MyD88) was part of the molecular response contributing to a pro-
[95]
[94]
inflammatory environment post-SE . Matsuda et al. reported that microglia secrete TNF-α to decrease
the proliferation of neural progenitor cells (NPCs) in the subgranular zone (SGZ) and demonstrated that
microglial activation is partly mediated through TLR9 post-SE. These studies emphasize the need for a
better understanding of the role of cytokine signaling post-seizure.

NEUROGENESIS
Neurogenesis, the incorporation of new neurons into the hippocampus, is a controlled process that affects
fundamental brain activities such as memory formation and learning. Neurogenesis, and the newborn cells
generated, contribute to brain plasticity and can be followed through maturation using specific markers.
The progression from newborn cells to mature neurons can be tracked using markers such as Nestin and
Sox-2 for newborn cells, doublecortin and polysialylated neuronal cell adhesion molecule for immature
[96]
neural progenitor cells, and NeuN for mature neurons . In recent years, there has been an increased effort
to determine some of the major regulators of the neurogenic process in the adult brain [97-99] . Neurogenesis,
mediated by the activation and differentiation of adult neural stem cells (NSCs), has been documented to
occur primarily in two regions of the adult CNS: the subventricular zone (SVZ) of the lateral ventricles,
and within the SGZ of the dentate gyrus (DG) in the hippocampus [100,101] . Neurogenesis in the hippocampus
will be the main focus of this section, as the hippocampal region has been intimately linked and affected by
seizures and epilepsy.