Viral infections of the central nervous system (CNS) can result in encephalitis. Viral encephalitis is a risk factor for epilepsy. Epilepsy has an incidence of about 1 to 3% and affects about 2.5 million Americans and more than 50 million individuals worldwide. Seizures result from imbalances between excitatory and inhibitory inputs within the brain. Encephalitis and resulting damage to the CNS can alter these inputs. Infection- initiated seizure disorders are often refractory to many established anti-epileptic drugs. Approximately 30% of individuals with epilepsy are refractory to currently existing anti-seizure medications. Therefore, finding new biological models for epilepsy and potentially new therapeutics are important for the public health. Different virus infections can cause encephalitis that result in seizures. These viruses include herpes viruses such as human herpes virus type-6, influenza viruses, rotaviruses, adenovirus, respiratory syncytial virus and picornaviruses. For example, the human picornavirus, Enterovirus 71, causes encephalitis where patients often present with seizures. A problem that has plagued this field is that a good experimental animal model is not available to investigate how virus encephalitis can lead to epilepsy. Previous animal models have infected rabbits, rats and mice with different viruses. These animals develop acute encephalitis and develop seizures but succumb to the infection. Theiler's murine encephalomyelitis virus (TMEV) is a neurotropic picornavirus. We have developed a new and novel model where infection of C57BL/6 mice with the Daniels virus (DAV) strain of TMEV leads to acute seizures between days 3 and 10 post infection. Mice recover but after a variable latent period mice start to have spontaneous seizures. This is the first infection driven model of temporal lobe epilepsy. We propose to test in Specific Aim 1 the hypothesis that direct virus infection of pyramidal cells of the hippocampus leads to the development of seizures.
In Specific Aim 2 we hypothesize that DAV infection targets a cytokine storm to regions within the CNS that leads to neuronal dysfunction and death. Relevance: Up to 20% of individuals who survive viral encephalitis develop epilepsy. This model is the first infection driven model for epilepsy. Other animal models use electrical stimulation or neurotoxic substances that kill and/or alter neurons in different parts of the brain leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies using an anti- inflammatory approach. As mentioned above about 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new approaches are warranted.
Viral infections of the central nervous system result in encephalitis. Viral encephalitis is associated with an increased risk for seizures and the development of epilepsy. We have developed a new and novel mouse model of virus-induced epilepsy. Other animal models for epilepsy use electrical stimulation or neurotoxic substances that kill and/or alter neurons within the CNS leading to spontaneous seizures. Our viral model is potentially more relevant particularly for the testing of new therapeutic strategies that use an anti-inflammatory approach. About 30% of individuals with epilepsy are refractory to existing anti-seizure medications, and recently the FDA is recommending that warnings be attached to eleven epilepsy drugs disclosing the risk of suicide. Therefore, new and novel approaches to this disease are warranted.
|Zhan, Jie; Lin, Tsen-Hsuan; Libbey, Jane E et al. (2018) Diffusion Basis Spectrum and Diffusion Tensor Imaging Detect Hippocampal Inflammation and Dendritic Injury in a Virus-Induced Mouse Model of Epilepsy. Front Neurosci 12:77|
|DePaula-Silva, Ana Beatriz; Sonderegger, F Lynn; Libbey, Jane E et al. (2018) The immune response to picornavirus infection and the effect of immune manipulation on acute seizures. J Neurovirol 24:464-477|
|Patel, Dipan C; Wallis, Glenna; Dahle, E Jill et al. (2017) Hippocampal TNF? Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy. eNeuro 4:|
|DePaula-Silva, Ana Beatriz; Hanak, Tyler J; Libbey, Jane E et al. (2017) Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy. J Neuroimmunol 308:30-42|
|Libbey, Jane E; Cusick, Matthew F; Doty, Daniel J et al. (2017) Complement Components Are Expressed by Infiltrating Macrophages/Activated Microglia Early Following Viral Infection. Viral Immunol 30:304-314|
|Cusick, Matthew F; Libbey, Jane E; Doty, Daniel J et al. (2017) The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis. J Neurovirol 23:696-703|
|Vezzani, Annamaria; Fujinami, Robert S; White, H Steve et al. (2016) Infections, inflammation and epilepsy. Acta Neuropathol 131:211-234|
|Libbey, Jane E; Hanak, Tyler J; Doty, Daniel J et al. (2016) NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection. Exp Neurol 280:89-96|
|Libbey, Jane E; Doty, Daniel J; Sim, Jordan T et al. (2016) The effects of diet on the severity of central nervous system disease: One part of lab-to-lab variability. Nutrition 32:877-83|
|Smeal, R M; Fujinami, R; White, H S et al. (2015) Decrease in CA3 inhibitory network activity during Theiler's virus encephalitis. Neurosci Lett 609:210-5|
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