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Sensitization of Ion Channels Contributes to Central and Peripheral Dysfunction in Neurofibromatosis Type 1

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Abstract

Neurofibromatosis type 1 (Nf1) is a progressive, autosomal disorder with a large degree of variability and severity of manifestations including neurological, cutaneous, ocular/orbital, orthopedic, and vascular abnormalities. Nearly half of Nf1 patients presents with cognitive impairment, specifically spatial learning deficits. These clinical manifestations suggest a global impairment of both central and peripheral nervous system functions in neurofibromatosis. Nf1 encodes for neurofibromin, a Ras GTPase-activating protein (Ras GAP) that has been implicated in the regulation of long-term potentiation (LTP), Ras/ERK (extracellular signal-regulated kinase) signaling, and learning in mice. Over the last decades, mice with a targeted mutation in the Nf1 gene, Nf1 −/− chimeric mice, Nf1 exon-specific knockout mice, and mice with tissue-specific inactivation of Nf1 have been generated to model the human Nf1 disease. These studies have implicated neurofibromin in regulation of the release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hippocampus and frontal lobe, which can regulate memory. Mutations in neurofibromin thus lead to perturbed ERK signaling, which alters GABA release, LTP, and subsequently leads to learning deficits. In addition to these cognitive deficits, Nf1 patients also have defects in fine and gross motor coordination as well as decreased muscle strength. Although the mechanisms underlying these motor deficits are unknown, deficits in GABAergic neurotransmission in both the motor cortex and cerebellum have been suggested. In this review, we present evidence to support the hypothesis that alterations of ion channel activity in Nf1 underscore the dysregulated neuronal communication in non-neuronal and neuronal cells that likely contributes to the clinical cornucopia of Nf1.

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Acknowledgments

This work was supported by a Neurofibromatosis New Investigator Award Nf1000099 from the Department of Defense Congressionally Directed Military Medical Research and Development Program and a Children's Tumor Foundation, Synodos for NF1 grant to R.K. A.M. was partially supported by a Young Investigator Award from the Children’s Tumor Foundation.

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  1. Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, 85742, USA

    Aubin Moutal, Erik T. Dustrude & Rajesh Khanna

  2. Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ, 85742, USA

    Rajesh Khanna

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Moutal, A., Dustrude, E.T. & Khanna, R. Sensitization of Ion Channels Contributes to Central and Peripheral Dysfunction in Neurofibromatosis Type 1. Mol Neurobiol 54, 3342–3349 (2017). https://doi.org/10.1007/s12035-016-9907-1

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