Preliminary Seizure Susceptibility and Threshold Characterization in Mouse Models Relevant to Angelman Syndrome and Chromosome 15q11.2-13 Duplications

Background: Maternally derived duplications or triplications of 15q11.2-q13 (Dup15q) are one of the most common genetic variations associated with autism spectrum disorder (ASD) detected in ~1-3% of cases (Glessner et al., 2009; Pinto et al., 2010; Moreno-De-Luca et al., 2013) and are characterized by seizures, developmental delay, and minor dysmorphic features (Finucane et al., 1993, Bolton et al., 2001; Urraca et al., 2013). The severity of symptoms correlates with the number of copies of the region with interstitial duplications, causing mild to moderate phenotypes, and isodicentric duplications, associated with severe phenotypes. Angelman Syndrome (AS) is a rare (1 in 15,000 births) neurologic disorder characterized by a wide range of symptoms including intellectual disabilities, lack of speech, ataxia, and seizures (Williams et al., 2006; Jiang et al., 1998). Both AS and Dup15q are believed to be caused by the loss or overexpression, respectively, of the ubiquitin protein ligase E3A (UBE3A) (Beaudet, 2011; McNamara & Isles, 2013). While divergent in gene dosage of UBE3A, both neurodevelopmental disorders exhibit high incidence of seizures.

Objectives: The present experiments were designed to evaluate seizure phenotypes, seizure susceptibility and threshold in mutant mouse models of Dup15q and AS. To identify neuroanatomical phenotypes in these mouse models magnetic resonance imaging (MRI) was used.

Methods: Breeding pairs were purchased from The Jackson Laboratory. Mice were bred in a conventional mouse vivarium at the University of California Davis School of Medicine. We quantified spontaneous seizure occurrence through video recordings and EEG in a home-cage environment. In cases where no spontaneous seizures were observed, we tested the threshold of inducible seizures by latencies to myoclonic jerk, generalized clonic-tonic seizure, and tonic extension or death using chemoconvulsants (pentylenetetrazole [40-80 mg/kg] and/or kainite acid [20-40 mg/kg]) and/or the Ugo Basile electroconvulsive device. Whole brains were harvested from an independent cohort of mice, and ex-vivo structural MRI was performed to identify volume changes in different brain regions associated with seizure susceptibility, as previously described (Ellegood et al., 2015).

Results:  No spontaneous seizures were observed in mice with deletions or overexpression of Ube3a. Ube3a overexpression mice did, however, exhibit faster onset to generalized clonic seizure and reduced latencies to tonic extension and death. Both deletion and overexpressing Ube3a mutant mice showed smaller hippocampal volume (p<0.05) when compared to WT controls. Data are currently being collected for seizure susceptibility in mutant mice with deletions in Ube3a.

Conclusions:  We detected significant outcomes due to the level of expression of Ube3a on a variety of seizure parameters as well as neuroanatomical measures, suggesting that these mouse models are useful preclinical tools for studying neurobiological mechanisms behind epilepsy and seizure impairments in Dup15q, AS, and ASD.