Journal Article

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome

Born, Heather A., Berg, Elizabeth L., Anderson, Anne E., Petkova, Stela P., Silverman, Jill L., Adhikari, Anna

2021

Overview

Background Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A ( UBE3A ), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems. Methods We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes. Results Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition. Limitations The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy. Conclusions Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Alleles / Angelman Syndrome / Angelman Syndrome - drug therapy / Angelman Syndrome - genetics / Angelman Syndrome - metabolism / Animals / Autism / Behavior / Brain - metabolism / Communication / Disease Models, Animal / Electroencephalography / Human Genetics / IGF / Insulin / Insulin-like growth factor / Insulin-Like Growth Factor II - genetics / Insulin-Like Growth Factor II - metabolism / Insulin-Like Growth Factor II - therapeutic use / Insulin-like growth factors / Laboratory animals / Males / Medicine / Medicine & Public Health / Memory / Mice / Mouse model / Neurodevelopmental disorders / Neurology / Neuropsychology / Neurosciences / Pediatrics / Psychiatry / Rats / Ube3a / Ubiquitin / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism