Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Mar;62(3):647-658.
doi: 10.1111/epi.16814. Epub 2021 Jan 21.

Augmented seizure susceptibility and hippocampal epileptogenesis in a translational mouse model of febrile status epilepticus

Kevin D Chen  1 , Alicia M Hall  1 , Megan M Garcia-Curran  2 , Gissell A Sanchez  1 , Jennifer Daglian  1 , Renhao Luo  1 , Tallie Z Baram  1   2   3
Affiliations

Augmented seizure susceptibility and hippocampal epileptogenesis in a translational mouse model of febrile status epilepticus

Kevin D Chen et al. Epilepsia. 2021 Mar.

Abstract

Objective: Prolonged fever-induced seizures (febrile status epilepticus [FSE]) during early childhood increase the risk for later epilepsy, but the underlying mechanisms are incompletely understood. Experimental FSE (eFSE) in rats successfully models human FSE, recapitulating the resulting epileptogenesis in a subset of affected individuals. However, the powerful viral and genetic tools that may enhance mechanistic insights into epileptogenesis and associated comorbidities, are better-developed for mice. Therefore, we aimed to determine if eFSE could be generated in mice and if it provoked enduring changes in hippocampal-network excitability and the development of spontaneous seizures.

Methods: We employed C57BL/6J male mice, the strain used most commonly in transgenic manipulations, and examined if early life eFSE could be sustained and if it led to hyperexcitability of hippocampal networks and to epilepsy. Outcome measures included vulnerability to the subsequent administration of the limbic convulsant kainic acid (KA) and the development of spontaneous seizures. In the first mouse cohort, adult naive and eFSE-experiencing mice were exposed to KA. A second cohort of control and eFSE-experiencing young adult mice was implanted with bilateral hippocampal electrodes and recorded using continuous video-electroencephalography (EEG) for 2 to 3 months to examine for spontaneous seizures (epileptogenesis).

Results: Induction of eFSE was feasible and eFSE increased the susceptibility of adult C57BL/6J mice to KA, thereby reducing latency to seizure onset and increasing seizure severity. Of 24 chronically recorded eFSE mice, 4 (16.5%) developed hippocampal epilepsy with a latent period of ~3 months, significantly different from the expectation by chance (P = .04). The limbic epilepsy that followed eFSE was progressive.

Significance: eFSE promotes pro-epileptogenic network changes in a majority of C57BL/6J male mice and frank "temporal lobe-like" epilepsy in one sixth of the cohort. Mouse eFSE may thus provide a useful tool for investigating molecular, cellular, and circuit changes during the development of temporal lobe epilepsy and its comorbidities.

Keywords: EEG; epilepsy; epileptogenesis; febrile seizures; genetics; hippocampus; in vivo electrophysiology; mouse; status epilepticus; temporal lobe epilepsy; transgenic.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

The authors do not have potential conflicts of interest to report.

Figures

FIGURE 1
FIGURE 1
Experimental febrile status epilepticus (eFSE) increases susceptibility to kainic acid (KA)–induced seizures later in life. A, The likelihood of developing severe seizures (measured by the Racine scale) after a given dose of KA, was compared in adult mice that had experienced eFSE (n = 16) and in control mice (n = 8). A trend for more severe seizures (median stage: control = 3; eFSE = 5) was not significant (Mann-Whitney U test, P = .18, Mann Whitney U = 42.50, 5). B, eFSE mice had a greater likelihood (56%) than control mice (25%) of reaching Racine stage 5 seizures (chi-square = 2.098, df = 1, P = .148) C, The Kolmogorov-Smirnov test excluded a normal distribution of the eFSE group, distinguishing mice affected by eFSE (responders; eFSE-R) and nonresponders (eFSE-NR), as described for rats. (Kolmogorov-Smirnov test, P = .0007). D, When analyzed for reaching seizure stage 5, eFSE-R differed significantly from both eFSE-NR and control mice (Kruskal-Wallis with Dunn correction for multiple comparisons, control vs eFSE-NR, P > .99, mean rank diff = 3.31; control vs eFSE-R, P = .009, mean rank diff = −9.74; eFSE-R vs eFSE-NR, P = .0004, mean rank diff = 13.06). **P < .01, ***P < .001. A and D are whisker-plots showing min-max as well as individual mouse values
FIGURE 2
FIGURE 2
Mice that experience experimental febrile status epilepticus (eFSE) have decreased latencies to kainic acid (KA)–induced seizures and augmented seizure propagation compared to controls. A, Latency to Racine stage 1 following KA administration was lower in eFSE mice vs controls (unpaired t test, t = 2.302, df = 22, P = .031; control mean = 244.6 ± 40.11 s; eFSE mean = 161 ± 16.42 s). B and C, compared with controls, eFSE mice were more likely to reach Racine stage 5 (see Figure 1A for statistical comparison), and no control mice reached stage 6 or 7
FIGURE 3
FIGURE 3
Graphic depiction of the experimental timeline to determine epileptogenesis and the timing of its onset. A, Experimental febrile status epilepticus (eFSE) took place at age 14–15 days, followed by bilateral intrahippocampal electroencephalography (EEG) electrode implantation surgery at 2 months of age and the initiation of continuous digital-EEG/video recordings. B, Graph depicting individual mice in the three experimental groups: eFSE (n = 24); normothermic/euthermic controls (n = 7); and hyperthermic controls (HT-CTL, in which hyperthermia was induced and eFSE prevented using diazepam, n = 3). The timing of the eFSE is indicated with the light pink vertical line. The onset of spontaneous seizures is shown as short red bars
FIGURE 4
FIGURE 4
Representative electroencephalography (EEG) recordings from a control mouse and four epileptic mice. A, Bilateral intrahippocampal EEG recordings from a control mouse. B, Representative EEG examples of seizures from the epileptic eFSE mice. The typical progression of electrographic hippocampal seizures is apparent, followed by a postictal suppression of the background. For all EEG traces, the scale on the left is in millivolts. The scale bar for each tracing is denoted in red, with the vertical bar representing 0.5 mV, and the horizontal bar representing 1 s
FIGURE 5
FIGURE 5
Quantitative characterization of the hippocampal epilepsy resulting from experimental febrile status epilepticus (eFSE) in mice. A, The cumulative number of seizures for each of the four epileptic eFSE mice. B, The cumulative seizure burden for the three mice recorded for more than a week after their first spontaneous seizure fits an exponential growth curve (eFSE-5: R2 = .963, df = 12; eFSE-6: R2 = .991, df = 31; eFSE-21: R2 = .932, df = 16). C, The total number of seizures per day for each epileptic mouse. D, The average daily seizure duration for each epileptic mouse. E, The average seizure duration per day fit with a linear regression for each mouse had a non-zero slope, consistent with increased duration over time eFSE-5: F = 24.31, DFn = 1, DFd = 10, P = .0006; eFSE-6: F = 31.13, DFn = 1, DFd = 25, P = <.0001; eFSE-21: F = 16.51, DFn = 1, DFd = 13, P = .0013). F, The total daily time spent in seizures for each epileptic mouse increased progressively with time. This is apparent using linear regression (linear regression eFSE-5: F = 5.25, DFn = 1, DFd = 10, P = .044; eFSE-6: F = 55.79, DFn = 1, DFd = 25, P = <.0001; eFSE-21: F = 8.14, DFn = 1, DFd = 13, P = .0014)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia. 1996;37(2):126–33. - PubMed
    1. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med. 1987;316(9):493–8. - PubMed
    1. Patterson KP, Baram TZ, Shinnar S. Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics. 2014;11:242–50. - PMC - PubMed
    1. French JA, Williamson PD, Thadani VM, Darcey TM, Mattson RH, Spencer SS, et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol. 1993;34(6):774–80. - PubMed
    1. Hesdorffer DC, Allen Hauser HW. Febrile seizures and the risk for epilepsy. In Baram TZ, Shinnar S editors. Febrile seizures. Massachusetts: Academic Press, 2002; p. 63–76.

Publication types