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Molecular and behavioral consequences of Ube3a gene overdosage in mice
A. Mattijs Punt, Matthew C. Judson, Michael S. Sidorov, Brittany N. Williams, Naomi S. Johnson, Sabine Belder, Dion den Hertog, Courtney R. Davis, Maximillian S. Feygin, Patrick F. Lang, Mehrnoush Aghadavoud Jolfaei, Patrick J. Curran, Wilfred F.J. van IJcken, Ype Elgersma, Benjamin D. Philpot
A. Mattijs Punt, Matthew C. Judson, Michael S. Sidorov, Brittany N. Williams, Naomi S. Johnson, Sabine Belder, Dion den Hertog, Courtney R. Davis, Maximillian S. Feygin, Patrick F. Lang, Mehrnoush Aghadavoud Jolfaei, Patrick J. Curran, Wilfred F.J. van IJcken, Ype Elgersma, Benjamin D. Philpot
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Research Article Neuroscience

Molecular and behavioral consequences of Ube3a gene overdosage in mice

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Abstract

Chromosome 15q11.2–q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome–based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2–q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.

Authors

A. Mattijs Punt, Matthew C. Judson, Michael S. Sidorov, Brittany N. Williams, Naomi S. Johnson, Sabine Belder, Dion den Hertog, Courtney R. Davis, Maximillian S. Feygin, Patrick F. Lang, Mehrnoush Aghadavoud Jolfaei, Patrick J. Curran, Wilfred F.J. van IJcken, Ype Elgersma, Benjamin D. Philpot

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Figure 5

Ube3aOE mice show no deficits in cognitive performance.

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Ube3aOE mice show no deficits in cognitive performance.
(A) Schematic o...
(A) Schematic of the fear conditioning paradigm. (B–D) Comparisons of context-specific freezing behavior among WT, Ube3a+2, and Ube3a+4 mice. (B) Graph of baseline freezing expressed as percentage of total time. (C and D) Mean ± SEM freezing time 24 hours (C) and 28 days (D) after conditioning to ascertain short- and long-term fear-memory, respectively. One-way ANOVA and Tukey’s post hoc test. (E–G) Spatial memory acquisition as determined from the Morris water maze paradigm. Heatmap visualization and mean ± SEM graphing of average time spent by WT (E), Ube3a+2 (F), and Ube3a+4 (G) mice in maze quadrants Q1, Q2, and Q3 and the platform containing the target quadrant (TQ). Repeated-measures 1-way ANOVA, with Dunnett’s post hoc test. (H) Schematic of the experimental timeline for the magazine training (MAG), acquisition (ACQ), and extinction (EXT) tests (top) and of the operant conditioning chambers (bottom). Behavioral chambers contained a food magazine and 2 nose-poke apertures. Gray indicates the presence of food reward (MAG, ACQ); white indicates the absence of reward (EXT). Yellow indicates the presence of the light cue; black, its absence. (I) Left to right: Graphs of mean ± SEM rewarded nose pokes during MAG training, days to reach operant acquisition criteria, and raw correct and incorrect responses at ACQ criteria with computed response accuracy (proportion of correct responses to the cued aperture). Unpaired 2-tailed t test. (J and K) Graphs of mean ± SEM cued (J) and non-cued (K) responses over the last 5 days of ACQ and during each day of EXT. Left: Raw responses. Right: Normalized responses (to the group means of cued responses during the last 5 days of ACQ). Two-way ANOVA, Bonferroni’s post hoc. *P < 0.05, **P < 0.01, ***P < 0.001.

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