Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle acti
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Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle activity in vivo Kazuo Kunisawa1,2,5, Nobuhiko Hatanaka2,3* , Takeshi Shimizu1,2,7, Kenta Kobayashi2,4, Yasuyuki Osanai1,2, Akihiro Mouri5, Qian Shi6, Manzoor A. Bhat6, Atsushi Nambu2,3 and Kazuhiro Ikenaka1,2
Abstract Paranodal axoglial junctions are essential for rapid nerve conduction and the organization of axonal domains in myelinated axons. Neurofascin155 (Nfasc155) is a glial cell adhesion molecule that is also required for the assembly of these domains. Previous studies have demonstrated that general ablation of Nfasc155 disorganizes these domains, reduces conduction velocity, and disrupts motor behaviors. Multiple sclerosis (MS), a typical disorder of demyelination in the central nervous system, is reported to have autoantibody to Nfasc. However, the impact of focal loss of Nfasc155, which may occur in MS patients, remains unclear. Here, we examined whether restricted focal loss of Nfasc155 affects the electrophysiological properties of the motor system in vivo. Adeno-associated virus type5 (AAV5) harboring EGFP2A-Cre was injected into the glial-enriched internal capsule of floxed-Neurofascin (NfascFlox/Flox) mice to focally disrupt paranodal junctions in the cortico-fugal fibers from the motor cortex to the spinal cord. Electromyograms (EMGs) of the triceps brachii muscles in response to electrical stimulation of the motor cortex were successively examined in these awake mice. EMG analysis showed significant delay in the onset and peak latencies after AAV injection compared to control (Nfasc+/+) mice. Moreover, EMG half-widths were increased, and EMG amplitudes were gradually decreased by 13 weeks. Similar EMG changes have been reported in MS patients. These findings provide physiological evidence that motor outputs are obstructed by focal ablation of paranodal junctions in myelinated axons. Our findings may open a new path toward development of a novel biomarker for an early phase of human MS, as Nfasc155 detects microstructural changes in the paranodal junction. Keywords: Paranodal junction, Multiple sclerosis, Electromyogram, Motor system, Neurofascin155 Introduction Oligodendrocytes are glial cells that extend myelin membranes around axons in the central nervous system (CNS) [2, 22]. Myelin facilitates saltatory conduction and provides metabolic support to axons [13, 30]. The predominant interaction site between myelin and an axon is formed by the paranodal junction adjacent to the node of Ranvier [33]. Nodes of *Correspondence: [email protected] 3 Division of System Neurophysiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki 444‑8585, Japan Full list of author information is available at the end of the article
Ranvier and paranodal junctions flanking the nodes are an important structure supporting saltatory conduction [15]. Rapid transmission of nerve impulses by saltatory conduction is indispensable of normal functio
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