31517
Neurophysiological Outcomes in a Preclinical Model of Ube3a Overexpression and Dup15q Syndrome
Copy number variants (CNV) are among the most common genetic causes of autism spectrum disorders (ASD), with 10-20% of cases resulting from one or more CNVs. Maternally derived duplications or triplications of 15q11.2-q13 (Dup15q syndrome) are the most penetrant CNV observed in ASD, accounting for up to ~3% of ASD cases (Glessner et al., 2009; Pinto et al., 2010). Dup15q syndrome, as a genetically defined subtype of ASD, also shares the core transcriptomic signature observed in idiopathic ASD (Ohta et al., 2015). Characteristic features of Dup15q syndrome are moderate to severe intellectual disability, seizures, hypotonia, speech impairments, anxiety, impaired motor coordination, and ASD (Cook et al., 1997; Bolton et al., 2001; Hogart et al., 2010; Urraca et al., 2013; Conant et al., 2014; Finucane BM et al., 2016). We and others postulate that overexpression of the E3 ubiquitin ligase gene (UBE3A), a critical gene in this region, contributes to the Dup15q syndrome phenotype.
Objectives:
To examine neurophysiology by electroencephalographic (EEG) for spiking events in our Ube3aoverexpression model system.
To investigate EEG characteristics such as epileptiform activity, total spectral power, and spectral power by band width frequency that are translationally relevant and observed in the Dup15q clinical population (e.g., high beta power measured in children with Dup15q).
Methods:
Wildtype and Ube3a overexpression mouse EEG was recorded over a24-48hr acquisition period (N=8-10/per genotype/per sex). EEG data were collected using the DSI telemetry system. Subjects were implanted with F20-EET telemeters bearing two channels to measure EEG and EMG. EEG leads were attached to surgical screws in the skull (anterior to the ICV coordinates), and EMG leads were placed in the trapezius muscles. Relative to bregma, EEG leads were located 1.0mm, 0.5mm for the positive channel and -1.0mm, -0.7mm for the negative counterpart. Animals were given one week to recover from surgery prior to data acquisition. Data were analyzed by DSI Neuroscore software and customized Matlab algorithms.
Results:
Previously, we discovered that neuronal specific overexpression of Ube3a isoform 2 is sufficient to cause seizures, behavioral and anatomical phenotypes (Copping et al., 2017). We extended our initial seizure data herein by reporting subthreshold seizure activity and an approximate 2-3 fold increase in spike train activity (0.5 s minimum duration and a minimum of 4 spiking events). Interestingly, we also observed increased beta spectral power without increased total power.
Conclusions:
Ube3a overexpression mice exhibited higher beta spectral power compared to their WT littermate controls, recapitulating the increased beta power signature seen in the clinical population and highlighting the use of spectral power as a biomarker for therapeutic efficacy. Seizures and epileptiform signatures in EEG can be similarly measured in both rodents and humans, and thus EEG phenotypes, such as those described herein, have realistic translational relevance (Featherstone et al., 2015; Modi and Sahin, 2017; Dickinson et al., 2018).