Ultrastructural changes in the striatum of the Slitrk5-/- mouse model of obsessive-compulsive disorder using volume electron microscopy

Studies in obsessive-compulsive disorder have suggested rare, damaging coding variants in the SLIT and NTRK-like 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. • Absence of Slitrk5 increases axonal degeneration risk in OCD mouse model • Ultrastructural analysis uncovers Wallerian-like degenerations in myelinated axons • Volumetric electron microscopy analysis of condensed axoplasm and myelin whorls • Slitrk5 Knockout shows reduced g-ratio and Nodes of Ranvier of myelinated axons • Excessive microglial phagocytosis indicates neuroinflammation in Slitrk5 -/-