Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome

Abstract

Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum disorder (ASD). Although ∼40 genes are located in the 15q11.2-q13.3 region, overexpression of the ubiquitin-protein E3A ligase (UBE3A) gene is thought to be the predominant molecular cause of the phenotypes observed in Dup15q syndrome. The UBE3A gene demonstrates maternal-specific expression in neurons and loss of maternal UBE3A causes Angelman syndrome, a neurodevelopmental disorder with some overlapping neurological features to Dup15q. To directly test the hypothesis that overexpression of UBE3A is an important underlying molecular cause of neurodevelopmental dysfunction, we developed and characterized a mouse overexpressing Ube3a isoform 2 in excitatory neurons. Ube3a isoform 2 is conserved between mouse and human and known to play key roles in neuronal function. Transgenic mice overexpressing Ube3a isoform 2 in excitatory forebrain neurons exhibited increased anxiety-like behaviors, learning impairments, and reduced seizure thresholds. However, these transgenic mice displayed normal social approach, social interactions, and repetitive motor stereotypies that are relevant to ASD. Reduced forebrain, hippocampus, striatum, amygdala, and cortical volume were also observed. Altogether, these findings show neuronal overexpression of Ube3a isoform 2 causes phenotypes translatable to neurodevelopmental disorders.

Genetic mutations in Ca2+ signaling alter dendrite morphology and social approach in juvenile mice

“…In order to determine whether genotype‐dependent changes in dendritic morphology are associated with changes in behavior, we used the three‐chambered social approach task to assess social behavior in juvenile mice of each genotype. This test was chosen because it is a simple, automated and standardized assay that can be used with juvenile animals . Mice were initially allowed to explore the empty left and right chambers during a 10 minutes habituation period.…”

“…The three‐chambered social approach was conducted as described previously . Animals were moved to the room 1 hour prior to testing.…”

“…The three-chambered social approach was conducted as described previously. [44][45][46][47] Animals were moved to the room 1 hour prior to testing. Testing was conducted during the light phase.…”

Glial overexpression of Dube3a causes seizures and synaptic impairments in Drosophila concomitant with down regulation of the Na+/K+ pump ATPα

“…More recently, overexpression of Ube3a limited to neurons was not associated with seizures in mice but was linked to seizure-induced decreased sociability (Krishnan et al, 2017). Elevated levels of Ube3a in excitatory neurons in mice caused increased anxiety-like behaviors, cognitive impairments, and reduced seizure threshold to pharmacologically induced seizures with pentylenetetrazol, however spontaneous seizures have not been observed in these mice (Copping et al, 2017). In summary, mouse models of Dup15q which focus on neuronal overexpression of Ube3a have failed to recapitulate the spontaneous Dup15q seizure phenotype.…”

MRI to Assess Neurological Function

“…This of course provides a challenge to mouse models, wherein classic modeling of individual causative genes results in a series of models of those genes, with the link to the entire spectrum uncertain. We have set out to phenotype as many mouse models related to autism as possible (examples include Copping et al., ; Jacob Ellegood, Henkelman, & Lerch, ; Gompers et al., , among others), and tried to synthesize similarities and differences across those models in a large‐scale analysis of 26 such mouse models (Ellegood et al., ). Our finding of convergence and divergence highlights the diversity present in the autistic spectrum.…”