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Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology
Alexia M Thomas1, Michael D Schwartz1, Michael D Saxe2
1Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA.
Sleep
|April 2, 2017
Summary
Comparing Cntnap2 knockout rats and mice reveals distinct epilepsy and autism spectrum disorder phenotypes. These rodent models offer insights but highlight the need for cross-species analysis in disease research.
Area of Science:
- Neuroscience
- Genetics
- Comparative Biology
Background:
- Recent advancements allow rodent genome modification, raising questions about their utility as human disease models.
- The gene contactin-associated protein-like 2 (Cntnap2) is linked to cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD).
Purpose of the Study:
- To compare the electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2.
- To evaluate the translational relevance of Cntnap2 knockout rodent models for human diseases.
Main Methods:
- Male Cntnap2 knockout (KO) and wild-type (WT) rats and mice underwent telemeter implantation for continuous EEG, electromyogram, body temperature, and locomotor activity monitoring.
- Animals were assessed using an ASD-related behavioral test battery, followed by 24-hour EEG recordings analyzed for sleep-wake parameters and spectral analysis.
Main Results:
- Cntnap2 KO rats displayed severe motor seizures, hyperactivity, and consolidated sleep-wake patterns.
- Cntnap2 KO mice exhibited absence seizure-like events, hypoactivity, and fragmented wakefulness.
- Both KO models showed reduced alpha-band EEG spectral power during wakefulness, indicating a conserved biomarker.
Conclusions:
- Deletion of Cntnap2 results in divergent behavioral and EEG phenotypes between rats and mice, differing in nature and severity.
- Neither rodent model fully recapitulates the complete spectrum of CDFE and ASD symptoms.
- Cross-species comparisons are crucial for understanding conserved gene functions and the limitations of single-species models for human disease research.