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. 2021 Jun;20(5):e12727.
doi: 10.1111/gbb.12727. Epub 2021 Mar 4.

Impaired instrumental learning in Spred1-/- mice, a model for a rare RASopathy

Sarah C Borrie  1 , Alexa E Horner  2 , Akihiko Yoshimura  3 , Eric Legius  1 , Maksym V Kopanitsa  2   4 , Hilde Brems  1
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Free article

Impaired instrumental learning in Spred1-/- mice, a model for a rare RASopathy

Sarah C Borrie et al. Genes Brain Behav. 2021 Jun.
Free article

Abstract

RASopathies are neuro-cardio-facio-cutaneous disorders stemming from mutations in genes regulating the RAS-MAPK pathway. Legius syndrome is a rare RASopathy disorder caused by mutations in the SPRED1 gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS/RAF and by its interaction with neurofibromin, a Ras GTPase-activating protein (RAS-GAP). Cognitive impairments have been reported in Legius syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a Spred1 mouse model for Legius syndrome has demonstrated spatial learning and memory deficits, but other cognitive domains remained unexplored. Here, we attempted to utilize a cognitive touchscreen battery to investigate if Spred1-/- mice exhibit deficits in other cognitive domains. We show that Spred1-/- mice had heterogeneous performance in instrumental operant learning, with a large subgroup (n = 9/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS-MAPK signalling pathway could rescue these cognitive impairments, Spred1-/- mice were acutely treated with the clinically relevant mitogen-activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that Spred1-/- mice can model severe cognitive impairments that cannot be reversed in adulthood.

Keywords: MEK inhibition; RAS-MAPK; RASopathy; autism spectrum disorder; cognitive impairment; instrumental learning; mouse; neurodevelopmental disorder; spred1; touchscreen test.

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