Evaluation of a TrkB agonist on spatial and motor learning in the Ube3a mouse model of Angelman syndrome

Abstract

Angelman syndrome is a rare neurodevelopmental disorder caused by a mutation in the maternal allele of the gene Ube3a. The primary symptoms of Angelman syndrome are severe cognitive deficits, impaired motor functions, and speech disabilities. Analogous phenotypes have been detected in young adult Ube3a mice. Here, we investigate cognitive phenotypes of Ube3a mice as compared to wild-type littermate controls at an older adult age. Water maze spatial learning, swim speed, and rotarod motor coordination and balance were impaired at 6 mo of age, as predicted. Based on previous findings of reduced brain-derived neurotrophic factor in Ube3a mice, a novel therapeutic target, the TrkB agonist 7,8-DHF, was interrogated. Semichronic daily treatment with 7,8-DHF, 5 mg/kg i.p., did not significantly improve the impairments in performance during the acquisition of the water maze hidden platform location in Ube3a mice, after training with either massed or spaced trials, and had no effect on the swim speed and rotarod deficits. Robust behavioral phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Our results suggest that motor deficits could offer useful outcome measures for preclinical testing of many pharmacological targets, with the goal of reducing symptoms in adults with Angelman syndrome.

Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model

“…BDNF has a well-established role as a regulator of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Reduced levels of BDNF signaling have been reliably observed in the AS mouse model [68,69]. Previously, our team reported BDNF-induced signaling requires TrkB association with PSD-95, and disruption of this association, in the AS mouse model, which likely underlies AS deficits in learning and memory [30,31] and elevated seizure and spike train phenotypes.…”

Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice

“…Moreover, among studies that have tested novel therapeutic approaches in AS model mice, some of the highly reproducible behavioral phenotypes are more frequently rescued than others. Across 16 recent studies that were able to rescue at least one of the behaviors tested here, motor coordination deficits on the rotarod were most commonly corrected, with the phenotype completely or partially rescued in over half of the studies (nine of 16: Adhikari et al., 2021 ; Cruz et al., 2021 ; Guzzetti et al., 2018 ; Judson et al., 2021 ; Kumar et al., 2019 ; Schmid et al., 2021 ; Silva‐Santos et al., 2015 ; Van Woerden et al., 2007 ; Wolter et al., 2020 ) and no rescue in the rest of the studies (Berg et al., 2020 ; Gu et al., 2019 ; Hethorn et al., 2015 ; Milazzo et al., 2021 ; Schultz & Crawley, 2020 ; Sonzogni et al., 2018 ; Wang et al., 2019 ). Partial or complete rescue occurred least frequently in open field thigmotaxis (one of four studies in which it was examined: Guzzetti et al., 2018 ) and marble burying (four of 10 studies in which it was examined: Cruz et al., 2021 ; Judson et al., 2021 ; Schmid et al., 2021 ; Silva‐Santos et al., 2015 ).…”

Forestwalk: A machine learning workflow brings new insights into posture and balance in rodent beam walking

“…We focused on comparing transgenic mouse strains used to study Angelman syndrome (AS), which is a genetic disorder affecting the nervous system, and is characterized by developmental delay, intellectual disability, profound speech impairment, and problems with movement and balance (39,52). The rotarod is most often used to study balance and coordination in mouse models for AS, and has identified impaired performance across several transgenic lines (42,43,53) and been used to assess therapeutic interventions (54)(55)(56)(57)(58). A particular strength of the beam walk in comparison to the rotarod is that it enables an assessment of how the animal performs the test, not only if the animal performs it (9).…”