701. MODELLING COGNITIVE AND PSYCHIATRIC BEHAVIOURAL TRAITS IN A MOUSE MODEL OF NEUROFIBROMATOSIS TYPE I

Abstract Background Neurofibromatosis type I (NF1) is caused by a mutation in one copy of the neurofibromin 1 gene. Patients exhibit diverse symptoms, including tumour formation, hyperpigmentation, and vision disorders. A majority also experience learning difficulties and psychiatric conditions like ADHD, autism, anxiety, or depression, which standard therapies do not address. Aims & Objectives In this research we aimed to replicate and expand the currently published behavioural characterisation of the heterozygous Nf1 mouse model (Nf1 +/-), in order to establish its suitability in future preclinical drug trials specifically targeting cognitive and neuropsychiatric symptoms in NF1 patients. Method The initial approach involved the phenotypic characterisation of the Nf1 +/- mouse model using a broad battery of standard rodent behavioural tests, and then a set of touchscreen-based tests, to examine specific aspects of cognition (including attention, working memory, short-term memory, spatial memory, associative memory, cognitive flexibility), social function, and psychiatric traits (including anxiety and depression-like behaviours). We also measured whole brain weight upon dissection. Results Male and female Nf1 +/- mice showed globally reduced cognitive performance and an increase in traits relevant to autism, but no changes in emotionality or locomotion, according to integrative behavioural analyses. Touchscreen testing was then employed to evaluate sustained attention using the rodent continuous performance test (rCPT). Initial evaluation of performance in this task revealed specific attentional deficits in Nf1 +/- mice. This was not confounded by differential reward motivation, as shown by the touchscreen progressive ratio task. Brain weights of Nf1 +/- mice were significantly higher compared to controls, and several behavioural measures correlated with brain weights, providing supportive evidence for a mechanistic link. Discussion & Conclusions We were able to build on published findings regarding behavioural alterations in the Nf1 +/- mouse model, and found important additional phenotypes relevant to NF1. As consistent evidence shows higher brain volumes in NF1 patients, the +/- mouse model will be extremely useful in investigating the underlying neurobiological mechanisms. Furthermore, the alterations in behaviour relevant to cognition and psychiatric phenotypes support the use of this mouse model in future trials testing pharmacological therapeutics for these symptom complexes in NF1 patients.