Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model
Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel, Steven A. Kushner, Ype Elgersma
Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel, Steven A. Kushner, Ype Elgersma
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Research Article Genetics

Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.

Authors

Sara Silva-Santos, Geeske M. van Woerden, Caroline F. Bruinsma, Edwin Mientjes, Mehrnoush Aghadavoud Jolfaei, Ben Distel, Steven A. Kushner, Ype Elgersma

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Figure 4

Ube3a reactivation in juvenile animals does not recover epilepsy susceptibility, but Schaffer collateral–CA1 LTP is fully recovered.

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Ube3a reactivation in juvenile animals does not recover epilepsy suscep...
(A) Epilepsy susceptibility in Ube3aStop/p+;CreERT+ mice persists after Ube3a gene reactivation at a juvenile age (n = 8 mice/group). (B) The induction of tonic-clonic seizures induced by audiogenic stimulation (indicated by the red arrows) is efficiently treated by administration of AEDs (blue rectangle illustrates treatment administration and wash-out period) in adult Ube3aStop/p+;Cre– (n = 2) and Ube3am–/p+ (n = 12) mice. Seizures reappeared 3 days after cessation of treatment. Percentages indicate the amount of mutant mice that developed seizures upon audiogenic stimulation (see also Supplemental Methods for more experimental details). Hippocampal plasticity deficit as measured by LTP in mutant mice is ameliorated upon gene reactivation at both (C) juvenile and (D) adult ages. Data represent mean ± SEM. Two-way ANOVA with genotype and treatment as independent variables was used for statistical testing. All tests showed a significant effect of genotype (see also Supplemental Table 2 for statistical comparisons). Number of slices/mouse used: juvenile reactivation: WT;CreERT+ Veh. (n = 16/4), WT;CreERT+ Tamox. (n = 25/4), Ube3aStop/p+;CreERT+ Veh. (n = 22/4), Ube3aStop/p+;CreERT+ Tamox. (n = 22/5); adult reactivation: WT;CreERT+ Veh. (n = 18/6), WT;CreERT+ Tamox. (n = 37/8), Ube3aStop/p+;CreERT+ Veh. (n = 23/4), Ube3aStop/p+;CreERT+ Tamox. (n = 15/4). **P < 0.01.