| Description |
Epilepsy is the fourth most common neurological disorder and is characterized by excessive neuronal activity that results in seizures. Viral encephalitis is known to increase the risk for epilepsy by 16-fold, and, with over 100 viruses able to infect the human brain, viral encephalitis represents a significant risk factor for the development of epilepsy. Seizures are thought to be caused by an imbalance of excitatory and inhibitory neuronal inputs. Furthermore, the inflammatory cytokines tumor necrosis factor (TNF)-a and interleukin (IL)-6 have been shown to influence excitatory and inhibitory signaling in the brain. Investigating excitatory neurotransmission and the role of inflammatory signaling can help elucidate mechanisms of seizure generation and potential treatments. Our lab has developed a model of virus-induced epilepsy using the Theiler's murine encephalomyelitis virus (TMEV). When C57BL/6J mice are infected with this virus, they develop seizures during the infection (acute seizures) and although these mice eventually clear the virus, some animals go on to exhibit spontaneous recurrent seizures (Epilepsy). The mice in this model present with behavioral seizures along with astrogliosis, microglial activation, and degeneration in the hippocampus. We sought to further explore seizures in the TMEV model. First, we found that the glutamate receptor antagonist NBQX increased seizure numbers in TMEV-infected mice. Next, we utilized minocycline and wogonin, two anti-inflammatory compounds that reduce seizures in the TMEV model when given prior to infection, to test whether treatment at a iv later and clinically relevant time point could reduce seizures. However, seizures were not reduced when given 2 days post infection (DPI). Finally, we targeted the metabotropic glutamate receptor 5 (mGluR5), which reduces inflammation and provides neuroprotection in other models, in order to lower TNF-a and IL-6 production and reduce seizure outcomes in the acute phase of the TMEV model. We found that stimulation of mGluR5 with the selective positive allosteric modulator VU0360172 attenuated seizure outcomes and reduced the number of TNF-a positive immune cells at 3, but not 6, DPI. No significant reductions in IL-6 positive cells were observed. These results show that mGluR5 stimulation reduces TNF-a production and seizure outcomes in the TMEV model. |
