Abstracts

This is a Late-Breaking abstract.

Rationale: Microglia are the brain’s resident immune cells and professional phagocytes. Their activation, proliferation, and inflammatory responses are prominent features that occur in association with seizures and epilepsy. We and others recently found significant alterations of microglial phagocytosis-signaling molecules that include downregulation of Triggering Receptor Expressed On Myeloid Cells 2 (Trem2) in cortical brain tissues surgically resected from patients with drug-resistant epilepsy and in an experimental model of acquired temporal lobe epilepsy. Trem2 is a microglial receptor that contributes to the regulation of the survival and proliferation of these cells as well as to phagocytic responses and inflammatory control. Little is known on how Trem2 signaling contributes to the epilepsy neuropathology. Therefore, this study aimed to characterize the levels of Trem2 receptors and their relation to inflammation in human and experimental epilepsy.

Methods: Human cortical brain tissues surgically resected from patients with refractory epilepsy (n=34; males, n=17; females, n=17) were processed for Enzyme Linked Immunosorbent Assay (ELISA)-based multiplex analysis to measure Trem2 together with an array of inflammatory cytokines. Samples were obtained with patient consent and IRB approval. To determine Trem2 contribution to seizure-induced inflammation, we utilized pilocarpine to induce status epilepticus (SE) in wild type (WT) and Trem2 KO mice, and harvested hippocampal tissues following 1 hr of SE (n=4-5/group; males and females). Because Trem2 regulates microglial mTOR signaling we measured this pathway in parallel.

Results: In human epilepsy, Trem2 protein levels were significantly higher in brain tissues from male compared to female epileptic patients (p=0.03). This paralleled higher levels of the inflammatory cytokine IL-6 in males compared to females (p=0.08). In experimental epilepsy, we found that WT and Trem2 KO mice had similar pilocarpine-induced seizure and SE thresholds according to the Racine scale. Cytokine multiplex analysis showed higher levels of inflammatory molecules in hippocampi of Trem2 KO+SE male mice compared to WT+SE male mice (p < 0.05), while cytokine levels were highly variable in female mice (WT+SE or Trem2+SE). Interestingly, SE-induced increases in hippocampal mTOR activation were dampened in Trem2 KO mice.