Alterations of Caspr2 and Nav1.6 on myelinated axon damage in a rat model of chronic cerebral hypoperfusion.

Abstract

Myelinated axons require the correct localization of key proteins that are essential for nerve conduction and cognitive function. Little is known regarding the altered expression of contactin-associated protein 2 (Caspr2) at the juxtaparanodal regions and Nav1.6 at the node of Ranvier in response to chronic cerebral hypoperfusion (CCH). The aim of the present study was to examine the alterations in the key protein of myelinated axons and the potential mechanisms that may follow CCH. We established a rat model of CCH by controllable partial narrowing of bilateral common carotid arteries. Then, we detected cerebral blood flow (CBF) after surgery. We also evaluated motor-evoked potentials (MEPs), assessed the Morris water maze test, analyzed Caspr2 expression through immunohistochemistry and Nav1.6 protein expression through western blot analysis at 2, 4 and 12 weeks. The results revealed that the mean CBF value was significantly decreased to 33.90±5.48%. The MEP latencies and the escaping latencies were significantly prolonged. There was also an elongation of the first time passing of the hidden platform with a reduction of crossing platform times in spatial probing. Furthermore, the Caspr2 immunoreactivity demonstrated that the Caspr2 level was significantly downregulated with abnormal locations in the corpus callosum. The western blot analysis of Nav1.6 protein revealed that the level was reduced significantly over time. The results demonstrate that CCH leads to central conductive function loss, cognitive function damage and alterations in the key protein of myelinated axons, which may provide a molecular basis and key link for white matter damage.