Central Alteration in Peripheral Neuropathy of Trembler-J Mice: Hippocampal pmp22 Expression and Behavioral Profile in Anxiety Tests.

Juan Pablo Damián,Lucía Canclini,Paul Ruiz,Miguel Calero,Lucia Vázquez Alberdi,Gonzalo Rosso,María Vittoria Di Tomaso,Silvia Olivera Bravo,Natalia Uriarte,Mariana Martínez,Alejandra Kun

doi:10.3390/biom11040601

Abstract

Charcot–Marie–Tooth (CMT) type 1 disease is the most common human hereditary demyelinating neuropathy. Mutations in pmp22 cause about 70% of all CMT1. Trembler-J (TrJ/+) mice are an animal model of CMT1E, having the same spontaneous pmp22 mutation that is found in humans. We compared the behavior profile of TrJ/+ and +/+ (wild-type) in open-field and elevated-plus-maze anxiety tests. In these tests, TrJ/+ showed an exclusive head shake movement, a lower frequency of rearing, but a greater frequency of grooming. In elevated-plus-maze, TrJ/+ defecate more frequently, performed fewer total entries, and have fewer entries to closed arms. These hippocampus-associated behaviors in TrJ/+ are consistent with increased anxiety levels. The expression of pmp22 and soluble PMP22 were evaluated in E17-hippocampal neurons and adult hippocampus by in situ hybridization and successive immunohistochemistry. Likewise, the expression of pmp22 was confirmed by RT-qPCR in the entire isolated hippocampi of both genotypes. Moreover, the presence of aggregated PMP22 was evidenced in unmasked granular hippocampal adult neurons and shows genotypic differences. We showed for the first time a behavior profile trait associated with anxiety and a differential expression of pmp22/PMP22 in hippocampal neurons of TrJ/+ and +/+ mice, demonstrating the involvement at the central level in an animal model of peripheral neuropathy (CMT1E).

Highlights

Charcot–Marie–Tooth disease type 1 (CMT1) is the most common hereditary demyelinating neuropathy [1,2,3,4,5]
The name peripheral myelin protein was suggested by Snipes et al 1992, who reported that “PMP-22 is synthesized by Schwann cells and is a major component of Peripheral Nervous System (PNS), but not Central Nervous
Latency time to first movement was greater in TrJ/+ than +/+ mice (p = 0.001, two-tailed, Latency time to first movement was greater in TrJ/+ than +/+ mice (p = 0.001, twoMann–Whitney U = 0) (Figure 1A) but there were no significant differences between genotailed, Mann–Whitney U = 0) (Figure 1A) but there were no significant differences between types in the time spent in the center zone (p = 0.503, Mann–Whitney U = 40) (Figure 1B) and genotypes in the time spent in the center zone (p = 0.503, Mann–Whitney U = 40) (Figure 1B)

Summary

Introduction

Charcot–Marie–Tooth disease type 1 (CMT1) is the most common hereditary demyelinating neuropathy [1,2,3,4,5]. Alterations in the pmp gene are the most common cause of CMT1, along with hereditary neuropathy with liability to pressure palsy (HNPP) [6,7,8]. In addition to duplications (CMT1A) and deletions (HNPP), all pmp point mutations have recently been included as a subtype of CMT1, CMT1E. PMP22 is a hydrophobic integral membrane glycoprotein highly expressed in Schwann cell myelin. It is composed of 160 amino acids, with a molecular mass of 22 kDa and a single N-glycosylation site [9,10,11,12]. The name peripheral myelin protein was suggested by Snipes et al 1992, who reported that “PMP-22 is synthesized by Schwann cells and is a major component of Peripheral Nervous System (PNS), but not Central Nervous

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