Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice.
Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE).



To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)β.



Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE.



This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Paul Feder Laboratory on Alzheimer's disease research, Tel-Aviv University, Tel Aviv, Israel.
Adi
A
Gross
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|The Neuroscience Laboratory, Felsenstein Medical Research Center, Tel-Aviv University, Tel Aviv, Israel.|Department of Neurology, Rabin Medical Center, Petach Tikva, Israel.
Felix
F
Benninger
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Paul Feder Laboratory on Alzheimer's disease research, Tel-Aviv University, Tel Aviv, Israel.
Ravit
R
Madar
The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Paul Feder Laboratory on Alzheimer's disease research, Tel-Aviv University, Tel Aviv, Israel.
Tomer
T
Illouz
Department of Biology and Chemistry, Liberty University, Lynchburg, Virginia, U.S.A.
Kathleen
K
Griffioen
Department of Neurology, Rabin Medical Center, Petach Tikva, Israel.
Israel
I
Steiner
The Neuroscience Laboratory, Felsenstein Medical Research Center, Tel-Aviv University, Tel Aviv, Israel.
Daniel
D
Offen
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.|The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.|The Paul Feder Laboratory on Alzheimer's disease research, Tel-Aviv University, Tel Aviv, Israel.
Eitan
0000-0001-8474-1487
E
Okun
D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D010862:Pilocarpine / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000172:deficiency* / Q000235:genetics
D003292:Convulsants; D016207:Cytokines; D012333:RNA, Messenger; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D010862:Pilocarpine

SE
; Epileptogenesis; Microglia; Neuroinflammation; TLR3; Toll-like receptors