The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

Twele, Friederike; Töllner, Kathrin; Bankstahl, Marion; Löscher, Wolfgang

doi:10.1002/epi4.2

Cited by 35 publications

(60 citation statements)

References 56 publications

(195 reference statements)

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“…Knowledge of paroxysmal EEG activity in otherwise “normal” mice that are used as experimental controls is important because it may interfere with epilepsy or seizure models using such mouse strains. In outbred mouse strains such as NMRI or Swiss, no SWDs have been observed [100-102]. …”

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

“…In a subsequent study, we found that the mouse strain also affected the occurrence of different types of spontaneous electrographic seizures and their pharmacological sensitivity in this model [102]. The typical electrographic seizures observed in epileptic mice are high- voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs) [100-102].…”

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

“…The typical electrographic seizures observed in epileptic mice are high- voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs) [100-102]. Epileptic FVB/N mice predominantly exhibited frequent HVSWs, but only infrequent HPDs, whereas NMRI mice exhibited both HVSWs and HPDs.…”

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

“…Epileptic FVB/N mice predominantly exhibited frequent HVSWs, but only infrequent HPDs, whereas NMRI mice exhibited both HVSWs and HPDs. NMRI mice were more sensitive to the anti-seizure effect of carbamazepine than FVB/N mice [102]. …”

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

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The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

Löscher¹,

Ferland

Ferraro

2017

Epilepsy & Behavior

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It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals’ performance in behavioral tests that often accompany acute and chronic seizure testing.

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Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 99%

See 2 more Smart Citations

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

Löscher¹,

Ferland

Ferraro

2017

Epilepsy & Behavior

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“…This prompted us to perform a prospective study in which EEG alterations occurring in this model were compared with the EEGs in appropriate sham controls, using hippocampal electrodes and video‐EEG monitoring. For this study we chose male mice of the NMRI (Naval Medical Research Institute) outbred strain, a general‐purpose strain in many fields of biology as well as in pharmacology and toxicology, which was previously used for this model by our group and others . We expect that our study adds to the current discussion about how to best define a “seizure” in experimental models of acquired epilepsy and how careful study of control animals can clarify this issue .…”

mentioning

confidence: 99%

The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy: Lack of electrographic seizure‐like events in sham controls

et al. 2017

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SummaryObjectiveThere is an ongoing debate about definition of seizures in experimental models of acquired epilepsy and how important adequate sham controls are in this respect. For instance, several mouse and rat strains exhibit high‐voltage rhythmic spike or spike‐wave discharges in the cortical electroencephalogram (EEG), which has to be considered when using such strains for induction of epilepsy by status epilepticus, traumatic brain injury, or other means. Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of kainate are increasingly being used as a model of mesial temporal lobe epilepsy. We performed a prospective study in which EEG alterations occurring in this model were compared with the EEGs in appropriate sham controls, using hippocampal electrodes and video‐EEG monitoring.MethodsExperiments with intrahippocampal kainate (or saline) injections started when mice were about 8 weeks of age. Continuous video‐EEG recording via hippocampal electrodes was performed 6 weeks after surgery in kainate‐injected mice and sham controls, that is, at an age of about 14 weeks. Three days of continuous video‐EEG monitoring were compared between kainate‐injected mice and experimental controls.ResultsAs reported previously, kainate‐injected mice exhibited two types of highly frequent electrographic seizures: high‐voltage sharp waves, which were often monomorphic, and polymorphic hippocampal paroxysmal discharges. In addition, generalized convulsive clinical seizures were infrequently observed. None of these electrographic or electroclinical seizures were observed in sham controls. The only infrequently observed EEG abnormalities in sham controls were isolated spikes or spike clusters, which were also recorded in epileptic mice.SignificanceThis study rigorously demonstrates, by explicit comparison with the EEGs of sham controls, that the nonconvulsive paroxysmal events observed in this model are consequences of the induced epilepsy and not features of the EEG expected to be seen in some experimental control mice or unintentionally induced by surgical procedures.

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GluK2 Is a Target for Gene Therapy in Drug‐Resistant Temporal Lobe Epilepsy

Boileau

Deforges

Peret

et al. 2023

Annals of Neurology

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ObjectiveTemporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5‐containing kainate receptors (KARs). TLE patients are often resistant to anti‐seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE.MethodsWe combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug‐resistant TLE.ResultsHere, we confirmed the translational potential of KAR suppression using a non‐selective KAR antagonist that markedly attenuated interictal‐like epileptiform discharges (IEDs) in TLE patient‐derived hippocampal slices. An adeno‐associated virus (AAV) serotype‐9 vector expressing anti‐grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9‐anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs.InterpretationOur gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof‐of‐concept for a gene therapy approach targeting GluK2 KARs for drug‐resistant TLE patients. ANN NEUROL 2023

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The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

Cited by 35 publications

References 56 publications

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy: Lack of electrographic seizure‐like events in sham controls

GluK2 Is a Target for Gene Therapy in Drug‐Resistant Temporal Lobe Epilepsy

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