NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment

Vicki J. Swier; Katherine A. White; Pedro L. Negrão de Assis; Tyler B. Johnson; Hannah G. Leppert; Mitchell J. Rechtzigel; David K. Meyerholz; Rebecca D. Dodd; Dawn E. Quelle; Rajesh Khanna; Christopher S. Rogers; Jill M. Weimer

doi:10.1111/cts.13858

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NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment

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NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment

Vicki J. Swier, Katherine A. White, Pedro L. Negrão de Assis, Tyler B. Johnson, Hannah G. Leppert, Mitchell J. Rechtzigel, David K. Meyerholz, Rebecca D. Dodd, Dawn E. Quelle, Rajesh Khanna, …

Clinical and translational science, Vol.17(6), e13858

06/2024

DOI: 10.1111/cts.13858

PMCID: PMC11208292

PMID: 38932491

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Abstract

Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor‐predisposition disorder. 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 Nf1 mouse models, here we employ an NF1+/ex42del 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 NF1+/ex42del and wild‐type 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, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance‐preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del 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.

Details

Title: Subtitle: NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment
Creators: Vicki J. Swier - Sanford Research
Katherine A. White - Sanford Research
Pedro L. Negrão de Assis - Sanford Research
Tyler B. Johnson - Sanford Research
Hannah G. Leppert - Sanford Research
Mitchell J. Rechtzigel - Sanford Research
David K. Meyerholz - University of Iowa
Rebecca D. Dodd - University of Iowa
Dawn E. Quelle - University of Iowa
Rajesh Khanna - University of Florida
Christopher S. Rogers - Exemplar Genetics
Jill M. Weimer - University of South Dakota
Resource Type: Journal article
Publication Details: Clinical and translational science, Vol.17(6), e13858
DOI: 10.1111/cts.13858
PMID: 38932491
PMCID: PMC11208292
ISSN: 1752-8054
eISSN: 1752-8062
Number of pages: 14
Language: English
Date published: 06/2024
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984648354702771

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