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

Sarah C. Borrie, Alexa E. Horner, Akihiko Yoshimura, Eric Legius, Maksym V. Kopanitsa, Hilde Brems

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Article numbere12727
JournalGenes, Brain and Behavior
Issue number5
Publication statusPublished - 2021 Jun


  • MEK inhibition
  • RASopathy
  • autism spectrum disorder
  • cognitive impairment
  • instrumental learning
  • mouse
  • neurodevelopmental disorder
  • spred1
  • touchscreen test

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience


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