Abstracts

Rationale:
Temporal lobe epilepsy is the most prevalent form of acquired epilepsy and it is difficult to treat with current anti-seizure drugs. Thus, the development of new disease modifying therapies is important to treat and prevent seizures in high-risk groups. Although the precise mechanisms that lead to epilepsy remain unclear, evidence from experimental and clinical work suggests that brain inflammation is an important contributor. Inflammation can alter the excitatory/inhibitory balance among neurons and is a significant cause of acute seizures. Studies suggested a role for the gut microbiota in neuroinflammation. The gut microbiota is commensal microorganisms that co-exist in a symbiotic relationship with the host. An axis between the gut microbiota–central nervous system (CNS) has been proposed, suggesting multifaceted interactions where the gut community impacts immune responses that influence CNS homeostasis and inflammation. Recent studies have recognized the involvement of the gut microbiota in several neuroinflammatory diseases. However, the influence of the microbiota in the development of seizure/epilepsy remains unclear. In our mouse model of infection-driven epilepsy, mice intra-cranially (IC) infected with Theiler’s murine encephalomyelitis virus (TMEV) develop behavioral seizures 3-10 days post infection (dpi). Activation of the innate immune response and infiltration of macrophages into the CNS play a key role in seizure development. The ketogenic diet, which has been used to treat refractory epilepsy, may exert its effect by modulating the composition of the gut microbiota. Also, clinical studies demonstrated a correlation between antibiotic administration and increased risk of developing seizures. Thus, we hypothesized that gut dysbiosis induced by antibiotic treatment could alter seizure development by modulating CNS inflammation.
Method:
C56BL/6J mice received broad-spectrum antibiotics (0.5g/L of gentamycin/ampicillin/erythromycin/neomycin) in the drinking water (regular water for the controls) for 10 days. Mice were IC injected with 4x105 plaque forming units of TMEV and maintained on antibiotic/regular water. Handling-induced seizures were determined daily, from 3-7 dpi, and seizure severity was scored via the Racine scale. At 7 dpi, mice were euthanized, cells were isolated from the brains, and cell populations and their inflammatory states were determined by flow cytometry.
Results:
The number of mice that developed seizures and seizure severity were greater in antibiotic-treated mice compared to controls. Also, CNS-infiltrating macrophages were significantly increased in antibiotic-treated mice (p< 0.05) and these cells had increased activation towards an inflammatory phenotype (Ly6C+) (p< 0.05).
Conclusion:
Our studies indicate a role for the gut microbiota in the development of acute seizures and modulation of CNS inflammation following viral encephalitis. This study sets the stage for future work investigating the role of the gut microbiota in seizure/epilepsy development.
Funding:
:NIH/NINDS 5R01NS065714-08