Febrile seizures are the most common type of seizure seen in young children. Unfortunately, some children with prolonged febrile seizures appear to be at risk for long-term cognitive disturbances. Identifying those individuals at risk for cognitive impairment and discovering the responsible mechanisms would provide opportunities for therapeutic intervention. In preliminary studies through an R21 funding mechanism, we used an immature rat model of long experimental febrile seizures (EFS) and established that a subgroup of rats experiencing these seizures developed spatial memory impairment and aberrant place cell function during adulthood. These deficits in hippocampal-dependent spatial cognition were accompanied by elevated MRI T2 signals in the hippocampus one month after the seizures. These findings demonstrate for the first time a direct causal effect of EFS on function of specific neurons that govern memory performance suggesting that MRI might be a potentially predictive biomarker for individuals at risk for cognitive disturbances. Furthermore, we have found that MRI T2 signals in hippocampus one month after the seizures are associated with inflammatory activation but no overt cell death indicating that inflammatory mediators might contribute to both MRI abnormalities and neuronal dysfunction, providing a target for selective intervention. However, prior to the application of these findings to the management of children with FSE additional critical information is needed. It is not known if hippocampal MRI changes take place early enough to be predictive of cognitive defects, and thus useful for potential intervention or whether the observed cellular and cognitive impairments are result of the FSE or of ensuing epileptogenesis. Determining if hippocampal levels of the inflammatory cytokine interleukin (IL)-12 distinguish FSE rats that became epileptic from those who did not and if this cytokine is involved in the cognitive defects provoked by EFS is necessary. In this proposal we will assess whether the cognitive defects in a subset of rats experiencing FSE are predicted by selective MRI changes that are visible early after the seizures and whether the cognitive and place-cell defects after FSE emerge prior to, and independent from, the epileptogenic process and spontaneous seizures, and define the underlying mechanisms of such deficits. To ascertain whether inflammatory cytokine expression distinguishes rats with cognitive defects after FSE from those with intact hippocampus-dependent memory we will compare rats with and without cytokine changes after EFS. The results of this study will set the stage for therapeutic intervention in children at risk for cognitive problems following febrile seizures.

Public Health Relevance

By far, the most common type of seizure seen in young children occurs as a result of fever. While the outcome in most children with febrile seizures is favorable, a significant number have cognitive deficits following prolonged febrile seizures. Identifying children at risk for cognitive deficits following febrile seizures is important since this will provide opportunities for therapeutic intervention. In this study we will determine if MRI findings after febrile seizures are predictive of cognitive impairment and also study whether inflammation following febrile seizures is responsible for both the MRI changes and cognitive deficits.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS078279-04
Application #
8693036
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
05405
Barry, Jeremy M; Sakkaki, Sophie; Barriere, Sylvain J et al. (2016) Temporal Coordination of Hippocampal Neurons Reflects Cognitive Outcome Post-febrile Status Epilepticus. EBioMedicine 7:175-90
Holmes, Gregory L (2016) Effect of Seizures on the Developing Brain and Cognition. Semin Pediatr Neurol 23:120-6
Barry, Jeremy M; Holmes, Gregory L (2016) Why Are Children With Epileptic Encephalopathies Encephalopathic? J Child Neurol 31:1495-1504
Barry, Jeremy M; Tian, Chengju; Spinella, Anthony et al. (2016) Spatial cognition following early-life seizures in rats: Performance deficits are dependent on task demands. Epilepsy Behav 60:1-6
Brennan, Gary P; Dey, Deblina; Chen, Yuncai et al. (2016) Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks. Cell Rep 14:2402-12
Patterson, Katelin P; Brennan, Gary P; Curran, Megan et al. (2015) Rapid, Coordinate Inflammatory Responses after Experimental Febrile Status Epilepticus: Implications for Epileptogenesis. eNeuro 2:
Isaeva, Elena; Romanov, Arthur; Holmes, Gregory L et al. (2015) Status epilepticus results in region-specific alterations in seizure susceptibility along the hippocampal longitudinal axis. Epilepsy Res 110:166-70
Holmes, Gregory L; Tian, Chengju; Hernan, Amanda E et al. (2015) Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide. Neurobiol Dis 77:204-19
Isaev, D; Lushnikova, I; Lunko, O et al. (2015) Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis. Neurobiol Dis 78:68-76
Barry, Jeremy M; Choy, ManKin; Dube, Celine et al. (2015) T2 relaxation time post febrile status epilepticus predicts cognitive outcome. Exp Neurol 269:242-52

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