Ultrastructural Changes in the Striatum of the Slitrk5-/-Mouse Model of Obsessive-Compulsive Disorder Using Volume Electron Microscopy

Abstract

Studies in obsessive-compulsive disorder have suggested rare, damaging coding variants in the SLIT and NTRKlike family member 5 (Slitrk5) gene as possible contributors to the disorder. Here we identify previously unrecognized pathological changes in the dorsomedial striatum of a Slitrk5 knockout mouse model using serial block-face scanning electron microscopy. Following a combination of manual annotation and automatic segmentation, detailed 2D and 3D analyses of myelin, axons, and mitochondria revealed ultrastructural abnormalities in the myelinated axons resembling Wallerian degeneration challenging the current understanding of Slitrk5 ' s role, extending its importance beyond neurite outgrowth to maintaining axonal integrity. Additionally, we observed a marked reduction in the g-ratio, reduced node of Ranvier volume, as well as activated microglial phagocytosis of myelin debris indicating potential neuroinflammatory processes. These results suggest that the absence of Slitrk5 heightens the vulnerability of myelinated axons to degenerative processes, providing new insights into the molecular underpinnings of obsessive-compulsive disorder. Our findings emphasize the need to reconsider Slitrk5 ' s neuroprotective function and lay the foundation for further research on its role in other brain regions and its broader implications for neurodegenerative diseases.Sino-Danish Centre for Research and Education; Jascha Fonden, and Torben og Alice Frimodt FondenThis work was supported by Sino-Danish Centre for Research and Education, A.P. M ; oslash;ller Fonden, Jascha Fonden, and Torben og Alice Frimodt Fonden. The funders had no involvement in the study design, data collection, analysis, manuscript preparation, or decision to publish