{'fraction_non_alphanumeric': 0.033003300330033, 'fraction_numerical': 0.011221122112211221, 'mean_word_length': 5.767857142857143, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Impaired instrumental learning in Spred1−/− mice, a model for a rare RASopathy

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.