Characterization of the Epilepsy Phenotype in Mice Expressing a Focal Cortical Dysplasia Type Ii-associated MTOR Variant
Abstract number :
3.537
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
1624
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Minsung Kim, MS – The University of Texas at Dallas
Tejas Devata, BS – The University of Texas at Dallas
Lena Nguyen, PhD – The University of Texas at Dallas
Rationale: Focal cortical dysplasia type II (FCDII) is a neurodevelopmental disorder characterized by focal malformation of cortical development and intractable epilepsy. FCDII is caused by pathogenic variants in genes along the mTOR signaling pathway, which is crucial for cell growth and development. A large portion of FCDII cases is caused by somatic activating variants in the MTOR gene, leading to mTOR hyperactivation. Expression of activating MTOR variants in mice recapitulates key FCDII histopathological features and has been reported to cause spontaneous seizures. However, a detailed EEG characterization of the epilepsy phenotype is lacking. Here, we characterized the seizure phenotype and EEG activity resulting from focal cortical expression of the activating MTORS2215Y variant in mice.
Methods: The MTORS2215Y variant was introduced into neural progenitor cells that give rise to pyramidal neurons destined to layer 2/3 in the mouse medial prefrontal cortex (mPFC) via in utero electroporation. Continuous video-EEG recordings were performed to monitor epileptiform activity in 8 to 10-week-old adult mice. Mice were recorded for 10 consecutive days under a controlled 12:12-hour light:dark cycle.
Results: Mice expressing the MTORS2215Y variant exhibited spontaneous seizures associated with generalized tonic-clonic activity. The mean daily seizure frequency was 9.0 seizures/day in the MTORS2215Y mice and 0.0 seizures/day in the control mice (p=0.0121, Mann Whitney test, n=8/group). Frequent interictal epileptiform discharges, including isolated spikes, polyspikes, and spike-and-wave activity were also detected. Further analysis of the seizure occurrences revealed a circadian pattern of seizure events in the MTORS2215Y mice, with seizures predominantly occurring in the dark cycle (61.7%) compared to the light cycle (38.3%) (p=0.0234, Wilcoxon signed-rank test, n=8/group).
Conclusions: Our findings show that expression of the MTORS2215Y variant in mPFC pyramidal neurons induces recurrent spontaneous tonic-clonic seizures with distinct EEG abnormalities. Furthermore, the observation that seizures occur predominantly in the dark cycle, when mice are more active, highlights the importance of considering the circadian influences on seizure activity in this mouse model. Given the roles of circadian rhythms in the regulation of cortical excitability and the relationships between mTOR activity and circadian clock function, understanding the interaction between circadian rhythms and the mTOR pathway in the context of FCDII could provide new insights into the mechanism underlying epilepsy in this disorder.
Funding: None
Basic Mechanisms