Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication (Dup15q) syndrome

• Published in: Journal of neurodevelopmental disorders 2024-07, Vol.16 (1), p.39-16, Article 39
• Main Authors: Saravanapandian, Vidya, Madani, Melika, Nichols, India, Vincent, Scott, Dover, Mary, Dikeman, Dante, Philpot, Benjamin D, Takumi, Toru, Colwell, Christopher S, Jeste, Shafali, Paul, Ketema N, Golshani, Peyman
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Autism; Biomarkers; Chromosome Aberrations; Chromosomes, Human, Pair 15 - genetics; Comorbidity; Computer software industry; Disease Models, Animal; Dup15q syndrome; EEG; Electroencephalography; Female; GABA; Intellectual Disability; Lubrication and lubricants; Male; Medical research; Medicine, Experimental; Mice; Neurophysiology; Sleep; Sleep - genetics; Sleep - physiology; Sleep deprivation; Sleep Wake Disorders - genetics; Sleep Wake Disorders - physiopathology; Trisomy - genetics; Trisomy - physiopathology
• ISSN: 1866-1955; 1866-1947; 1866-1955
• DOI: 10.1186/s11689-024-09556-7

Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABA R) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABA Rs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p