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Page 238 Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02

The chemical induction of status epilepticus, usually by injection of kainic acid or pilocarpine [47,48] , can
result in animals exhibiting SRSs days to weeks after SE, and allows for the determination of post-seizure
changes in the brain neuropil. Models using chemoconvulsants and kindling have provided researchers
with a way to study changes in mossy fiber sprouting, neurogenesis, and neuroinflammation post-seizure.

MICROGLIA
Microglia, which make up approximately 10% of the brain’s cells, are the central nervous system’s primary
form of immune defense. Originally thought to only serve immune response functions, they are now
widely recognized to perform important functions that contribute to the development and maintenance
of a healthy brain. Microglia are dynamic cells that survey their environment for injury or infection.
[49]
Ramified microglia rapidly and constantly extend and retract their processes to assess the environment .
By evaluating their surroundings, microglia can actively participate in neurogenesis [50,51] , neurotrophic
[52]
[54]
[53]
functions , neuronal phagocytosis , modulation of axonal processes , synapse formation and
pruning [55-57] . It has also been proposed that microglia aid in neurotransmitter clearance, specifically
[58]
glutamate , due to their upregulation of glutamate transporter GLT-1 in a cortical injury model . Many
[59]
of these functions however, are reported to be similarly performed by astrocytes.
Microglial contribution to epileptogenesis
Models of epilepsy provide insight into neuronal and glial behavior post-seizure. Microglia sense the injury,
and their activation cascade is initiated [60,61] as they migrate to the region of insult, where they then remain
[62]
activated for about 4-5 weeks post-seizure , creating an inflammatory environment around the site of
[63]
seizure onset. The extent and duration of microglial activation depends on the model used . Most, though
[64]
not all, chronic seizure models of epileptogenesis present a persistent inflammatory state in neural tissue .
After an inciting event, inflammatory cascades can either begin in the CNS, or be activated by molecules
[65]
in the systemic circulation via breakdown of the BBB . The seizure-induced activation of microglia
11
can be visualized and followed non-invasively by positron emission tomography using C-PK11195, a
radiolabeled TSPO (a selective translocator protein) that is expressed at low levels in the healthy CNS, but
upregulated when neuroinflammation is initiated. Although TSPO does not distinguish between microglia
[66]
and infiltrating macrophages , its upregulation provides clear proof of the neuroinflammatory state of
post-seizure CNS. Acute neuroinflammation is thought to contribute to chronic neuroinflammation states
[67]
or worsen a pre-existing state . Understanding how and when microglia are activated after seizures,
and how they contribute over time to neuroinflammation may provide a target for downregulating or
attenuating epileptogenesis.

Cytokines are signaling molecules that modulate inflammatory responses and are produced by neurons
and glial cells after seizures. Interleukin-1β (IL-1β), IL-2, and IL-6 are present in the brain at low
[68]
concentrations, which increase post-seizure . Following seizures, mRNA expression of IL-1β, IL-6,
TNF-α, TGF-β, and vascular endothelial growth factor (VEGF) were all reported to be upregulated ithe
hippocampus. IL-1β may induce seizures by upregulating N-methyl-D-aspartate (NMDA) receptors on
[69]
post-synaptic cells . Studies also suggest that uncontrolled levels of IL-1β impair synaptic plasticity and
[70]
cause neuronal dysfunction . Other studies have demonstrated that IL-1β decreased GABA-mediated
[71]
neurotransmission, leading to neuronal hyperexcitability and seizures . When IL-1β activity was blocked,
acute or recurrent seizures were reduced in rodent models [38,72,73] . Anakinra, a recombinant IL-1 receptor
antagonist, was successfully used in a clinical study to treat febrile infection-related epilepsy syndrome
(FIRES), demonstrating that IL-1β may be a crucial target in controlling seizure recurrence . TNF-α
[74]
is released by microglia and astrocytes, when low levels of glutamate are detected, to maintain neuronal
excitation levels by upregulating synapses . TNF-α also increases microglial glutamate release through
[75]
[76]
glutaminase and gap junction regulation and regulates the adhesion molecule N-cadherin, which is