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As many as 70% of children with NF1 report difficulties with spatial\/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various <jats:italic>Nf1<\/jats:italic> mouse models, here we employ an <jats:italic>NF1<\/jats:italic><jats:sup><jats:italic>+\/ex42del<\/jats:italic><\/jats:sup> miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from <jats:italic>NF1<\/jats:italic><jats:sup><jats:italic>+\/ex42del<\/jats:italic><\/jats:sup> and wild\u2010type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, <jats:italic>NF1<\/jats:italic><jats:sup><jats:italic>+\/ex42del<\/jats:italic><\/jats:sup> miniswine demonstrated slower and shorter steps, indicative of a balance\u2010preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of <jats:italic>NF1<\/jats:italic><jats:sup><jats:italic>+\/ex42del<\/jats:italic><\/jats:sup> miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.<\/jats:p>","DOI":"10.1111\/cts.13858","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T05:45:39Z","timestamp":1719467139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>NF1<sup>+\/ex42del<\/sup><\/i> miniswine model the cellular disruptions and behavioral presentations of <scp>NF1<\/scp>\u2010associated cognitive and motor impairment"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7509-9920","authenticated-orcid":false,"given":"Vicki 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