Progressive white matter deficits caused by N-methyl-D-aspartate receptor deficiency Katheron Intson1, Matthijs van Eede2, Rehnuma Islam3, Marija Milenkovic1*, Ali Salahpour1, R. Mark Henkelman2, Amy J. Ramsey1,3* 1Department of Pharmacology & Toxicology, University of Toronto; 2Mouse Imaging Centre, Hospital for Sick Children, Toronto; 3Department of Physiology, University of Toronto *Corresponding Author
Despite patient heterogeneity, consistent evidence implicates both volumetric and connectivity-related changes to brain structures in schizophrenia, particularly in white matter structures. Given the compelling evidence linking alterations of the N-methyl-D-aspartate (NMDA) receptor system to schizophrenia, we investigated whether NMDA receptor knockdown causes structural changes in the brain. Additionally, we studied the developmental trajectory of these changes: like human patients, schizophrenia-relevant behaviors manifest in an age-dependent manner in our mice, and we wondered whether this was temporally correlated with structural changes. We conducted magnetic resonance imaging in Grin1 knockdown (GluN1KD) male mice (GluN1KD n=9-10; wildtype n=10) at 3, 6, and 12 weeks. (These mice have reduced NMDA receptor expression globally.) Deformation-based morphometry was used to assess neuroanatomical differences, and a stringent false discovery rate was set at 1%. We detected deficits in white matter tracts in GluN1KD mice that were first evident at 3 weeks; additional deficits were detected at 6 and 12 weeks. Accompanying these changes, we found increased glial fibrillary acidic protein immunofluorescent reactivity in white matter tracts. We also detected volumetric reductions in substantia nigra and striatum of GluN1KD mice at all three ages, and changes in limbic structures specific to 6 weeks of age. We conclude that NMDA receptor deficiency causes volume reductions in white matter and dopaminergic structures from early in development, while changes to limbic structures are age-specific. To explain this, we postulate that the white matter structural changes we observed are mediated by inflammatory events, while dopamine and limbic structural changes are mediated by disruptions to neuromaturational events. We propose that, in a chronic state of NMDA receptor hypofunction, oligodendroglial dysfunction and demyelination is mediated by overactivation of glutamate projection neurons that causes excitotoxicity and reactive gliosis.
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