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Legius syndrome is a rare RASopathy disorder caused by mutations in the <jats:italic>SPRED1<\/jats:italic> gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS\/RAF and by its interaction with neurofibromin, a Ras GTPase\u2010activating protein (RAS\u2010GAP). Cognitive impairments have been reported in Legius syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a <jats:italic>Spred1<\/jats:italic> 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 <jats:italic>Spred1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice exhibit deficits in other cognitive domains. We show that <jats:italic>Spred1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice had heterogeneous performance in instrumental operant learning, with a large subgroup (<jats:italic>n<\/jats:italic>\u00a0=\u20099\/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS\u2010MAPK signalling pathway could rescue these cognitive impairments, <jats:italic>Spred1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice were acutely treated with the clinically relevant mitogen\u2010activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that <jats:italic>Spred1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice can model severe cognitive impairments that cannot be reversed in adulthood.<\/jats:p>","DOI":"10.1111\/gbb.12727","type":"journal-article","created":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T07:32:01Z","timestamp":1614151921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Impaired instrumental learning in <i>Spred1<\/i><sup><i>\u2212\/\u2212<\/i><\/sup> mice, a model for a rare RASopathy"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6880-772X","authenticated-orcid":false,"given":"Sarah C.","family":"Borrie","sequence":"first","affiliation":[{"name":"Department of Human Genetics KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa 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