Generation and characterization of pilocarpine-sensitive C57BL/6 mice as a model of temporal lobe epilepsy

Bankstahl, Marion; Müller, Christine J.; Wilk, Esther; Schughart, Klaus; Löscher, Wolfgang

doi:10.1016/j.bbr.2012.02.004

Cited by 39 publications

(27 citation statements)

References 36 publications

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“…Interestingly, ICV administration of TGF-b1 induces a significant IL-6 upregulation in FVB/N but not in C57BL/6 mice. These results may at least partially underlie previous studies showing that C57BL/6 mice exhibit a general low sensitivity to seizure induction (43)(44)(45) and that FVB/N mice have a lower threshold than do C57BL/6 mice for seizure-induced cell death (29,30,46), further suggesting that IL-6 upregulation plays an important role in the brain inflammatory response associated with TGF-b-induced epileptogenesis.…”

Section: Discussionsupporting

confidence: 70%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6–treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1–induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte–neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

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Section: Discussionsupporting

confidence: 70%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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“…Published studies suggest differences between mouse strains with respect to their susceptibility to pilocarpine-induced seizures/SE and resulting neuropathology (Bankstahl et al, 2012;Schauwecker, 2012). FVB/N mice appear to exhibit high vulnerability compared with other inbred (C57BL/6) or outbred strains (CD1, NMRI) (Chen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…SE induction in mice was performed by fractionated pilocarpine injection. As described previously for C57BL/6 and NMRI mice (Gröticke et al, 2007;Bankstahl et al, 2012), SE development was preceded by immobility, head nodding, Straub tail, tremor, chewing, and at least one generalized clonic-tonic seizure (type 4 or 5 on the Racine scale). SE itself was characterized by continuous limbic seizure activity (head nodding, forelimb convulsions, infrequent generalized tonic-clonic seizures).…”

Section: Se Induction In Mdr1a/bmentioning

confidence: 99%

“…Unfortunately, SE induction and survival rates can dramatically differ not only between rodent strains (Chen et al, 2005;Winawer et al, 2007a,b), but also between animals of the same strain bred by different vendors and even between inbred mice originating from different breeding rooms of the same vendor (Borges et al, 2003;Bankstahl et al, 2009Bankstahl et al, , 2012Müller et al, 2009). The mechanisms underlying this variable efficacy of pilocarpine are unknown.…”

Section: Introductionmentioning

confidence: 99%

“…SE onset was defined as continuous ongoing seizure activity following occurrence of one or two generalized tonic-clonic seizures [stage 4 or 5 on the Racine scale (Racine, 1972)]. SE was characterized by head nodding in an upright (sitting) body position, Straub tail, and slight to moderate convulsions of forelimbs, sometimes interrupted by further generalized tonic-clonic seizures (see Bankstahl et al, 2012). Behavioral seizure activity and SE duration was confirmed by individual EEG recordings in a subset of animals (for methodological details, see Klein et al, 2015).…”

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confidence: 99%

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Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

Römermann

Löscher

Bankstahl

2015

The Journal of Pharmacology and Experimental Therapeutics

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As a result of the growing availability of genetically engineered mouse lines, the pilocarpine post-status epilepticus (SE) model of temporal lobe epilepsy is increasingly used in mice. A discrepancy in pilocarpine sensitivity in FVB/N wild-type versus P-glycoprotein (PGP)-deficient mice precipitated the investigation of the interaction between pilocarpine and two major multidrug transporters at the blood-brain barrier. Doses of pilocarpine necessary for SE induction were determined in male and female wild-type and PGP-deficient mice. Brain and plasma concentrations were measured following low (30-50 mg×kg 21 i.p.) and/or high (200 mg×kg 21 i.p.) doses of pilocarpine in wild-type mice, and mice lacking PGP, breast cancer resistance protein (BCRP), or both transporters, as well as in rats with or without pretreatment with lithium chloride or tariquidar. Concentration equilibrium transport assays (CETA) were performed using cells overexpressing murine PGP or BCRP. Lower pilocarpine doses were necessary for SE induction in PGP-deficient mice. Brain-plasma ratios were higher in mice lacking PGP or PGP and BCRP, which was also observed after pretreatment with tariquidar in mice and in rats. Lithium chloride did not change brain penetration of pilocarpine. CETA confirmed transport of pilocarpine by PGP and BCRP. Pilocarpine is a substrate of PGP and BCRP at the rodent blood-brain barrier, which restricts its convulsive action. Future studies to reveal whether strain differences in pilocarpine sensitivity derive from differences in multidrug transporter expression levels are warranted.

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C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a^+/− mouse model of Dravet syndrome

2018

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Summary Many disease‐relevant phenotypes modeled in inbred mice have been shown to be strain‐dependent, indicating the important influence of genetic background on disease phenotypes. Although C57BL/6 mice are one of the most commonly used inbred strains in laboratory research, there are multiple substrains (eg, B6J vs B6N) that have been separated for more than 50 years. Thus, understanding the substrain differences is important for scientific rigor and reproducibility. In this study, seizure susceptibility, spontaneous seizures, and survival were compared between Scn1a+/− mice on (C57BL/6J × 129S6/SvEvTac)F1 (F1J) vs (C57BL/6N × 129S6/SvEvTac)F1 (F1N) strain backgrounds. F1N.Scn1a+/− mice were more susceptible to hyperthermia‐induced seizures, yet had milder spontaneous seizures and improved survival relative to F1J.Scn1a+/− mice. Our results indicate that choice of C57BL/6 substrain may significantly alter disease phenotypes and should be considered carefully in experimental design using the Scn1a+/− Dravet mouse model, as well as other mouse models of epilepsy.

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Generation and characterization of pilocarpine-sensitive C57BL/6 mice as a model of temporal lobe epilepsy

Cited by 39 publications

References 36 publications

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a^+/− mouse model of Dravet syndrome

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Generation and characterization of pilocarpine-sensitive C57BL/6 mice as a model of temporal lobe epilepsy

Cited by 39 publications

References 36 publications

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a+/− mouse model of Dravet syndrome

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C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a^+/− mouse model of Dravet syndrome