Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep–Wake Physiology

Apr 2, 2017Sleep

Rats and mice without Cntnap2 show seizure-like brain activity and irregular sleep-wake patterns

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Abstract

Cntnap2 knockout (KO) rats exhibited severe motor seizures and hyperactivity, while KO mice showed absence seizure-like events and hypoactivity.

Cntnap2 KO rats demonstrated increased consolidation of wakefulness and REM sleep compared to wild-type rats.
Cntnap2 KO mice experienced wake fragmentation and reduced locomotor activity relative to wild-type mice.
Seizures in Cntnap2 KO rats were more similar to symptoms seen in cortical dysplasia-focal epilepsy patients than those in KO mice.
Both Cntnap2 KO rats and mice showed reduced spectral power in the alpha (9-12 Hz) range during wake, indicating a conserved EEG biomarker.
Differences in seizure types and phenotypic severity suggest limitations in using single species models for translational research in human diseases.

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STUDY OBJECTIVES: Although recent innovations have enabled modification of the rat genome, it is unclear whether enhanced utility of rodents as human disease models will result. We compared electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD).

METHODS: Male contactin-associated protein-like 2 (Cntnap2) knockout (KO) and wild-type (WT) rats and male Cntnap2 KO and WT mice were implanted with telemeters to record EEG, electromyogram, body temperature, and locomotor activity. Animals were subjected to a test battery for ASD-related behaviors, followed by 24-hr EEG recordings that were analyzed for sleep-wake parameters and subjected to spectral analysis.

RESULTS: Cntnap2 KO rats exhibited severe motor seizures, hyperactivity, and increased consolidation of wakefulness and REM sleep. By contrast, Cntnap2 KO mice demonstrated absence seizure-like events, hypoactivity, and wake fragmentation. Although seizures observed in Cntnap2 KO rats were more similar to those in CDFE patients than in KO mice, neither model fully recapitulated the full spectrum of disease symptoms. However, KOs in both species had reduced spectral power in the alpha (9-12 Hz) range during wake, suggesting a conserved EEG biomarker.

CONCLUSIONS: Deletion of Cntnap2 impacts similar behaviors and EEG measures in rats and mice, but with profound differences in nature and phenotypic severity. These observations highlight the importance of cross-species comparisons to understand conserved gene functions and the limitations of single- species models to provide translational insights relevant to human diseases.

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Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep–Wake Physiology

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