Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?
An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.
Sakic
B
B
Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. West, Hamilton, Ontario, Canada. sakic@mcmaster.ca
Kolb
B
B
Whishaw
I Q
IQ
Gorny
G
G
Szechtman
H
H
Denburg
J A
JA
D000818:Animals; D001284:Atrophy; D003520:Cyclophosphamide / Q000494:pharmacology*; D003712:Dendrites / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D009929:Organ Size; D010296:Parietal Lobe / Q000276:immunology / Q000473:pathology; D017966:Pyramidal Cells / Q000473:pathology* / Q000648:ultrastructure; D016622:Silver Staining
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide