Brain inflammation, neurodegeneration and seizure development following picornavirus infection markedly differ among virus and mouse strains and substrains

Bröer, Sonja; Käufer, Christopher; Haist, Verena; Li, Lin; Gerhauser, Ingo; Anjum, Muneeb; Bankstahl, Marion; Baumgärtner, Wolfgang; Löscher, Wolfgang

doi:10.1016/j.expneurol.2016.02.011

Cited by 66 publications

(74 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous vEEG experiments using cortical surface electrodes have demonstrated that TMEV-infected mice have limbic seizures that secondarily generalize during the acute infection period (Stewart et al, 2010a; Bröer et al, 2016). Because TMEV infection results in significant cell loss in the CA1 region and increased excitability in the CA3 region of the hippocampus, a brain region often associated with seizure initiation in TLE, we hypothesized that focal seizures occurring in the hippocampus might not have been observable with cortical electrodes as used in a prior study (Stewart et al, 2010a).…”

Section: Resultsmentioning

confidence: 99%

“…Theiler’s murine encephalomyelitis virus (TMEV)-infected C57BL/6J mice have acute seizures 3–8 days postinfection (dpi) and exhibit pathologic and physiologic changes such as astrogliosis, microgliosis, neuronal loss in CA1, and increased excitatory synaptic transmission in CA3 pyramidal neurons in the hippocampus. Importantly, the mice survive the infection, clear the virus from the brain, present with cognitive impairment and anxiety-like symptoms, and develop chronic spontaneous seizures (Libbey et al, 2008; Stewart et al, 2010a; Smeal et al, 2012; Umpierre et al, 2014; Bröer et al, 2016). Thus, TMEV-infected mice recapitulate many clinical observations from patients suffering from infection-induced temporal lobe epilepsy (TLE) and provide an opportunity to study the molecular mechanisms of infection-induced epileptogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

Patel

Wallis

Dahle

et al. 2017

eNeuro

100

View full text Add to dashboard Cite

Central nervous system infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler’s murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially that mediated by tumor necrosis factor-α (TNFα), in the development of acute seizures. TNFα modulates glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in TNFα signaling after TMEV infection might contribute to acute seizures. We found a significant increase in both mRNA and protein levels of TNFα and the protein expression ratio of TNF receptors (TNFR1:TNFR2) in the hippocampus, a brain region most likely involved in seizure initiation, after TMEV infection, which suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. An increase in hippocampal cell-surface glutamate receptor expression was also observed during acute seizures. Although pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of genetically modified animals deficient in either TNFα or TNFRs had robust changes in seizure incidence and severity after TMEV infection. TNFR2–/– mice were highly susceptible to developing acute seizures, suggesting that TNFR2-mediated signaling may provide beneficial effects during the acute seizure period. Taken together, the present results suggest that inflammation in the hippocampus, caused predominantly by TNFα signaling, contributes to hyperexcitability and acute seizures after TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated or augment TNFR2-mediated effects of TNFα may provide antiseizure and disease-modifying effects after central nervous system infection.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

Patel

Wallis

Dahle

et al. 2017

eNeuro

100

View full text Add to dashboard Cite

show abstract

“…This model was discovered and characterized at the University of Utah by Dr. Robert Fujinami, Dr. Steve White, and Dr. Karen Wilcox. It is notable that significant neuroinflammation might contribute to transient symptomatic seizures and subsequent epileptogenesis and behavioral deficits [23–25] seen in these mice and therefore, this model may be of particular interest for evaluating compounds that suppress the inflammatory response, which may contribute to epilepsy [24, 26–28]. The ETSP is currently exploring the effects of test compounds on the initial, transient phase of seizure susceptibility [23, 24].…”

Section: Etsp Compound Testing Paradigmsmentioning

confidence: 99%

The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP)

et al. 2017

View full text Add to dashboard Cite

For over 40 years, the National Institute of Neurological Disorders and Stroke/National Institutes of Health-funded Anticonvulsant Screening Program has provided a preclinical screening service for participants world-wide that helped identify/characterize new antiseizure compounds, a number of which advanced to the market for the treatment of epilepsy. The newly-renamed Epilepsy Therapy Screening Program (ETSP) has a refocused mission to identify novel agents which will help address the considerable remaining unmet medical needs in epilepsy. These include identifying antiseizure agents for treatment-resistant epilepsy, as well as anti-epileptogenic agents that will prevent the development of epilepsy or disease-modifying agents that will ameliorate or even cure established epilepsy and its comorbidities. This manuscript provides an overview of the ETSP’s efforts aimed at identifying the next generation of therapeutic agents to further reduce the suffering from and burden of epilepsy.

show abstract

“…In order to study the contribution of viral encephalitis to the development of acute seizures and epilepsy, our lab has developed an experimental mouse model of virus-induced seizures/epilepsy, which has now been used by several groups and similar results have been obtained (Broer et al, 2016; Libbey et al, 2008; Stewart et al, 2010b). In this model (Figure 1C, D), i.c.…”

Section: Seizures and Epilepsymentioning

confidence: 99%

Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

DePaula-Silva

Hanak

Libbey

et al. 2017

Journal of Neuroimmunology

View full text Add to dashboard Cite

Mouse models are great tools to study the mechanisms of disease development. Theiler’s murine encephalomyelitis virus is used in two distinct viral infection mouse models to study the human diseases multiple sclerosis (MS) and epilepsy. Intracerebral (i.c.) infection of the SJL/J mouse strain results in persistent viral infection of the central nervous system and a MS-like disease, while i.c. infection of the C57BL/6J mouse strain results in acute seizures and epilepsy. Our understanding of how the immune system contributes to the development of two disparate diseases caused by the same virus is presented.

show abstract

Brain inflammation, neurodegeneration and seizure development following picornavirus infection markedly differ among virus and mouse strains and substrains

Cited by 66 publications

References 66 publications

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy

The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP)

Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

Contact Info

Product

Resources

About