Most neurofibromatosis type 1 (NF1) patients present with neurological issues in parallel with abnormal brain white matter and myelin. Although links for NF1 neuropathophysiology and abnormal myelin were proposed long ago, no current data can openly support or refute this idea. Various studies suggest that Nf1 mutations affect myelin biology and function, but any impact on learning/memory remains unclear. Here, we show that mice with an Nf1 mutation induced in adult myelinating cells present learning, but not memory, issues in a voluntary fine motor skill test, the complex wheel (CW). The specific parameters shaping CW learning curves are differentially impacted in an Nf1 mutation dose- and gender-dependent manner and are responsive to nitric oxide modulation. Fate analyses of Nf1 mutant cells support links between defective myelin and fine motor learning issues. Our results diversify the potential therapeutic targets and windows of time for NF1 treatments that restore or improve myelin function.
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targeted Nf1 mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory–motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test—the complex wheel (CW; a wheel with unevenly spaced rungs)—to delineate fine motor skill learning curves following induction of an Nf1 mutation in pre-existing myelinating cells (pNf1 mice). We found that pNf1 mutant females experience delayed or impaired learning in the CW, while proper learning in pNf1 males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of an Nf1 mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1.
Hernandez, D. P., Cruz, D. M., Martinez, C. S., Garcia, L. M., Figueroa, A., Villarreal, M., ... & López-Juárez, A. (2024). Gender-Specific Fine Motor Skill Learning Is Impaired by Myelin-Targeted Neurofibromatosis Type 1 Gene Mutation. Cancers, 16(3), 477. https://doi.org/10.3390/cancers16030477
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