Abstracts

Rationale:
For centuries, sleep disturbances have been noted to be commonly associated with different forms of epilepsy. However, the extent, nature, and mechanisms of these abnormalities in distinct types of epilepsy are not fully elucidated. Malformations of cortical development, including FCD and MEG, are significant causes of severe epilepsy and intellectual disability. FCD is characterized by localized regions of aberrant cortical organization. MEG is defined by a broader overgrowth of cerebral structures. Both FCD and MEG have been strongly associated with mutations in PIK3CA, a gene in the PI3K-mTOR-AKT signaling pathway important for regulating cell growth, metabolism, survival, and proliferation during organogenesis. In prior work, we generated mouse models of PIK3CA-related FCD and MEG by activation of the E545K mutation in a subset or all central nervous system progenitor cells, respectively. These mouse models exhibit several defining pathological features of FCD and MEG, including epilepsy. In this study, we investigated abnormalities of sleep architecture associated with an FCD and MEG-causing Pik3ca mutation in mice.
Method:
FCD and MEG mutants and their respective controls were generated using LoxP-Cre technology. FCD mice were obtained by postnatal activation of the Pik3caE545K allele using Tamoxifen-inducible Nestin-cre. MEG mice were obtained by embryonic activation of the same allele with a constitutive Nestin-cre. To examine sleep architecture, a combined video/EEG/EMG recording was obtained from freely moving mice for 8 hours during the day. Behavioral states were classified as Wake, NREM, or REM sleep based on video observation, along with the level of activity in EEG and EMG quantified by power spectrum analysis. Sleep parameters including duration of different sleep states and sleep fragmentation were measured and compared between mutants and controls.
Results:
Relative to controls, the duration of total sleep was not different in either mutant group. But, the duration of REM sleep was significantly reduced, and as expected, the duration of NREM sleep was significantly increased in FCD mice. The incidence of brief wakes, a marker of sleep fragmentation, was substantially increased in both mutant groups. The incidence of sleep spindles, the hallmark of NREM sleep in EEG, was reduced in both mutant groups. Furthermore, during NREM sleep, both FCD and MEG mice displayed an elevated number of interictal spikes, characteristic of an epileptic brain. These epileptiform events disrupted the normal delta EEG patterns of this sleep stage.
Conclusion:
Our results demonstrate that Pik3caE545K mutation leads to similar impairments of sleep quality despite the pathological divergence in our mouse models of FCD and MEG. Further studies will explore the cellular and network mechanisms of these impairments and whether improving sleep quality may alleviate the severity of the epilepsy phenotype.
Funding:
:This study is supported by funding from CURE (FK) and National Institutes of Health, USA (1R01NS099027, KJM; 1R01NS102796, FK)