Anti-LINGO-1 antibody treatment improves chronic stress-induced spatial memory impairments and oligodendrocyte loss in the hippocampus

Abstract

Chronic exposure to stressful conditions may affect spatial learning and memory abilities and the brain structure, and disruptions in oligodendrocyte function may cause cognitive dysfunction. Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) is a potent negative regulator of oligodendrocytes and axon myelination. However, the questions we sought to answer in this study are whether hippocampal oligodendrocytes are involved in the pathological process of spatial learning and memory impairments induced by chronic stress (CS) and whether antibodies targeting LINGO-1 improve stress-induced spatial learning and memory impairments by protecting the hippocampal oligodendrocytes in stressed rats. After 4 weeks of CS, rats were randomly divided into either the CS standard group or anti-LINGO-1 group. The anti-LINGO-1 group was treated with an anti-LINGO-1 antibody (8 mg/kg) for 3 weeks; all rats were assessed in the Morris water maze. Immunohistochemical staining and modern stereological methods were used to precisely quantify the total number of 2′,3′-cyclic nucleotide 3′-phosphodiesterase-positive (CNPase+) oligodendrocytes in each subregion of the hippocampus. At the behavioural level, after three weeks of treatment, the anti-LINGO-1 group displayed significantly more platform crossings in the Morris water maze test than the CS standard group. The total swimming distance and swimming speed were not significantly different. In the open field test, the percentage of distance travelled in the central region did not differ between the CS standard group and control group or between the anti-LINGO-1 group and the CS standard group. Unbiased stereological analyses revealed significantly greater total numbers of CNPase+ cells in the CA3 and dentate gyrus (DG) areas of the hippocampus in the anti-LINGO-1 group than in the CS standard group. A significant difference in the total number of CNPase+ cells was not observed in the hippocampal CA1 region between the anti-LINGO-1 and CS standard groups. Based on the results of the present study, the anti-LINGO-1 antibody alleviated spatial memory impairments and protected oligodendrocytes in the hippocampus of chronically stressed rats.