In vivo ultrafast Doppler imaging combined with confocal mi-2 croscopy and behavioral approaches to gain insight into the cen-3 tral expression of Peripheral Neuropathy in Trembler-J Mice

Abstract

The main human hereditary peripheral neuropathy (Charcot-Marie-Tooth, CMT), manifests in progressive sensory and motor deficits. Mutations in the compact myelin protein gene pmp22 cause more than 50% of all CMTs. CMT1E, is a subtype of CMT1 myelinopathy carrying micro-mutations in pmp22. The Trembler-J mice have a spontaneous mutation in pmp22 identical to that present in a CMT1E human patients. PMP22 is mainly (but not exclusively) expressed in Schwann cells. Some studies have found the presence of pmp22 together with some anomalies in CNS of CMT patients. Recently, we identified the presence of higher hippocampal pmp22 expression and elevated levels of anxious behavior, in TrJ/+ compared to those observed in wt. In the present paper, we delve deeper into the central expression of the neuropathy modeled in Trembler-J analyzing in vivo the cerebrovascular component by Ultrafast Doppler, exploring the vascular structure by scanning laser confocal microscopy and analyzing the behavioral profile by anxiety and motor difficulties tests. We have found that TrJ/+ hippocampi have increased blood flow and a higher vessel volume compared with the wild type. Together with this, we found an anxiety-like profile in TrJ/+, and the motor difficulties described earlier. We demonstrate that there are specific cerebrovascular hemodynamics, associated to a vascular structure and anxious behavior associated with the TrJ/+ clinical phenotype, a model of the human CMT1E disease.