behavioral-characterization-of-an-angelman-syndrome-mouse-model

Behavioral Characterization of an Angelman Syndrome Mouse Model

This manuscript describes a battery of behavioral tests available to characterize Angelman syndrome (AS)-like phenotypes in an established murine model of ...

Institute of Molecular Genetics of the Czech Academy of Sciences

Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1 (SGIP1) interacts with cannabinoid CB receptors. SGIP1 is abundantly and principally expressed within the nervous system. SGIP1 and CB receptors co-localize in axons and presynaptic boutons. SGIP1 interferes with the internalization of activated CB receptors in transfected heterologous cells. Consequently, the transient association of CB receptors with β-arrestin2 is enhanced and prolonged, and CB receptor-mediated ERK1/2 signalling is decreased. Because of these actions, SGIP1 may modulate affect, anxiety, pain processing, and other physiological processes controlled by the endocannabinoid system (ECS).

SGIP1 is involved in regulation of emotionality, mood, and nociception and modulates in vivo signalling of cannabinoid CB receptors.

Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.

Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficits in maternally inherited . The disease is characterized by intellectual disability, impaired motor skills, and behavioral deficits, including increased anxiety and autism spectrum disorder features. The mouse models used so far in AS research recapitulate most of the cardinal AS characteristics. However, they do not mimic the situation found in the majority of AS patients who have a large deletion spanning 4-6 Mb. There is also a large variability in phenotypes reported in the available models, which altogether limits development of therapeutics. Therefore, we have generated a mouse model in which the  gene is deleted entirely from the 5' UTR to the 3' UTR of mouse  isoform 2, resulting in a deletion of 76 kb. To investigate its phenotypic suitability as a model for AS, we employed a battery of behavioral tests directed to reveal AS pathology and to find out whether this model better mirrors AS development compared to other available models. We found that the maternally inherited Ube3a-deficient line exhibits robust motor dysfunction, as seen in the rotarod and DigiGait tests, and displays abnormalities in additional behavioral paradigms, including reduced nest building and hypoactivity, although no apparent cognitive phenotype was observed in the Barnes maze and novel object recognition tests. The AS mice did, however, underperform in more complex cognition tasks, such as place reversal in the IntelliCage system, and exhibited a different circadian rhythm activity pattern. We show that the novel UBE3A-deficient model, based on a whole-gene deletion, is suitable for AS research, as it recapitulates important phenotypes characteristic of AS. This new mouse model provides complementary possibilities to study the  gene and its function in health and disease as well as possible therapeutic interventions to restore function.

Agnieszka Kubik-Zahorodna

Czech Centre for Phenogenomics

Institute of Molecular Genetics of the Czech Academy of Sciences

Behavioral Characterization of an Angelman Syndrome Mouse Model

Agnieszka Kubik-Zahorodna

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Institute of Molecular Genetics of the Czech Academy of Sciences

Behavioral Characterization of an Angelman Syndrome Mouse Model

Czech Centre for Phenogenomics