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. 2017 Aug:134:1-8.
doi: 10.1016/j.eplepsyres.2017.04.020. Epub 2017 Apr 30.

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

Timothy A Warner  1 , Zhong Liu  1 , Robert L Macdonald  2 , Jing-Qiong Kang  3
Affiliations

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

Timothy A Warner et al. Epilepsy Res. 2017 Aug.

Abstract

It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in SCN1A and GABRG2 genes. In patients, the onset of FS is likely due to the combined effect of temperature and inflammation in genetically vulnerable individuals because fever is often associated with infection. Much effort has been spent to understand the mechanisms underlying fever induction of seizures. In addition to the role of cytokines in FS, previous studies in Scn1a+/- knockout mice, a model of Dravet syndrome, indicated that temperature elevation alone could result in seizure generation, and the effect of elevated temperature inducing seizures was age-dependent. Here, we report the thermal effect in a different mouse model of Dravet syndrome, the Gabrg2+/Q390X knockin mouse. We demonstrated age-dependent dysregulated temperature control and that temperature elevation produced myoclonic jerks, generalized tonic clonic seizures (GTCSs) and heightened anxiety-like symptoms in Gabrg2+/Q390X mice. The study indicated that regardless of other inflammatory factors, brief heat alone increased brain excitability and induced multiple types of seizures in Gabrg2+/Q390X mice, suggesting that mutations like GABRG2(Q390X) may alter brain thermal regulation and precipitate seizures during temperature elevations.

Keywords: Electroencephalography; Febrile seizures; GABRG2(Q390X) mutation; Generalized tonic clonic seizures; Myoclonic jerks; Temperature.

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Conflict of interest statement

Disclosures

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this study is consistent with those guidelines.

Figures

Figure 1
Figure 1. Interictal and ictal EEG s in Gabrg2+/Q390X knockin mice
(A) Representative EEG recordings show that a 2 month old Gabrg2+/Q390X knockin mouse had spike-wave-discharges (SWDs). (B) The frequency of SWDs in Gabrg2+/Q390X mice was 4–7 Hz. (C) Spontaneous generalized tonic clonic seizures (GTCSs) were associated with epileptiform activity on EEG (D). Spontaneous myoclonic jerks were associated with spike discharges on EEG. (E) Average occurrences of GTCSs and myoclonic jerks (MJ) with noticeable behavioral seizures over 24 hours EEG recordings were measured in 2–4 month old mice (n = 31 for each genotype). (F,G) The pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) (F) or interleukin-1beta (IL-1β) (G) in 50 µl plasma from peripheral blood of mice untreated or treated at 42.5C for 30 min were measured with Elisa.
Figure 2
Figure 2. Temperature elevation and PTZ induced seizures and abnormal EEGs in Gabrg2+/Q390X knockin mice
(A) The temperature induction apparatus and heating setup are shown. (B) A diagram of the temperature induction and pentylenetetrazol (PTZ) seizure induction procedures are shown. (C) Sample EEGs traces are shown for 2–4 month old Gabrg2+/(Q390X) knockin mice during temperature elevation. (D) Sample EEGs traces are shown for 2–4 month old Gabrg2+/(Q390X) knockin mice during PTZ seizure induction. (E) Number of myoclonic jerks for 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice are plotted for baseline and for temperature elevation and PTZ seizure induction segments. (F) Frequency of SWDs for 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice are plotted for baseline, temperature induction, and PTZ segments. (Temperature seizure induction, n = 10 for wt and 10 for het; PTZ seizure induction, n = 6 for wt and 10 for het) (***p < 0.001 vs wt); (†† p < 0.01; ††† p < 0.001 vs baseline het).
Figure 3
Figure 3. Temperature elevation and PTZ induced seizure latency, severity, and survival in Gabrg2+/Q390X knockin mice
(A) The modified Racine scale used for seizure scoring is shown. (B, C) Latency to reach stages 2 and 3 of the modified Racine scale for 2–4 month old Gabrg2+/Q390X knockin mice in C57BL/6J (B) or DBA/2J (C) was plotted for temperature elevation and PTZ seizure inductions. (D,E) Percentage to reach stage 5 of the modified Racine scale was plotted for 2–4 month old Gabrg2+/Q390X knockin mice in C57BL/6J (D) or DBA/2J (E) during temperature elevation and PTZ seizure inductions. (F,G) Survival percentage following temperature and PTZ induction was plotted for 2–4 month old Gabrg2+/(Q390X) knockin mice in C57BL/6J (F) or DBA/2J (G) (In F, temperature seizure induction, n = 10 for wt and 10 for het; PTZ seizure induction, n = 6 for wt and 6 for het; in G, n = 6 for each genotype for temperature induction and n = 10 for each genotype for PTZ seizure induction).
Figure 4
Figure 4. Heat induced body temperature changes as well as seizures and anxiety-like phenotypes were differentially expressed in Gabrg2+/Q390X mice at different age
(A) The percentage of mice to reach 42.5 °C during temperature induction was plotted for P18–20 and 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice. (B) The rate of core body temperature change assessed over 2-minute intervals during temperature induction was plotted for P18–20 and 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice. (C) The number of myoclonic jerks during temperature induction was plotted for P18–20 and 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice. (D) The number of GTCS (GTCSs) during temperature induction was plotted for P18–20 and 2–4 month old wild-type (wt) and Gabrg2+/Q390X (het) mice. (E) Frequency of jumping bouts during temperature induction was plotted for P18–20 and 2–4 month old wild-type (wt) and Gabrg2+/Q390X knockin (het) mice (n = 10 for wt and het for 2–4 month old mice; n = 11 for wt and 14 for het for P18–20); (*p < 0.05 vs wt).
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References

    1. Duffner PK, Baumann RJ, Green JL. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. American Academy of Pediatrics. Steering Committee on Quality Improvement and Management. Subcommittee of Febrile Seizures. Pediatrics. 2008;121:1281–6. - PubMed
    1. Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. Acta neuropathologica. 2016;131:211–34. - PMC - PubMed
    1. Gatti S, Beck J, Fantuzzi G, Bartfai T, Dinarello CA. Effect of interleukin-18 on mouse core body temperature. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2002;282:R702–R709. - PubMed
    1. Millichap JG. STUDIES IN FEBRILE SEIZURES I. Height of Body Temperature as a Measure of the Febrile-seizure Threshold. Pediatrics. 1959;23:76–85. - PubMed
    1. Mulley JC, Scheffer IE, Petrou S, Berkovic SF. Channelopathies as a genetic cause of epilepsy. Current opinion in neurology. 2003;16:171–6. - PubMed

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