OLFACTORY DYSFUNCTION IN THE MRL MOUSE MODEL OF CNS SLE

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune / inflammatory disease that is frequently accompanied by brain atrophy and neuropsychiatric (NP) manifestations. CNS involvement ranges from focal abnormalities to diffuse disorders, and according to more recent clinical data, may also include olfactory dysfunction of unknown etiology. Similar to CNS SLE, spontaneous development of lupus-like disease in MRL/lpr mice coincides with neurodegeneration in periventricular regions and behavioural impairments in paradigms dependent on olfactory function. However, previous studies could not resolve whether exploration-dependant deficits reflect changes in emotional reactivity / exploratory drive, or altered olfactory capacity. The latter possibility was also supported by evidence of disturbed projection of neuroblasts to the olfactory bulb. The aim of this thesis was then to examine whether lupus-like autoimmunity alters olfactory function, thereby affecting performance in other behavioural tasks. Indeed, behavioural testing in a battery of paradigms revealed that lupus-prone MRL/lpr males spend less time exploring unfamiliar conspecifics and demonstrate age-dependant changes in responsiveness to attractant and repellant scents. Sustained treatment with the immunosuppressant cyclophosphamide abolished signs of autoimmunity and improved responsiveness to an attractant and a novel object, thus indirectly supporting a cause-effect relationship. In order to probe for pathogenic autoimmune factors, we administered CSF from CNS SLE patients and purified autoantibodies into the brains of healthy mice. Sustained infusion of autoimmune CSF induced olfactory dysfunction, excessive immobility in the forced swim test, enhanced perseveration in a learning task, and altered several home-cage behaviours. Direct exposure to purified antibodies produced broad, but relatively mild, functional changes in olfactory function, spatial learning / memory, and home-cage behaviour. These findings provide an initial step toward understanding the nature and immunopathogenic mechanisms underlying early neurofunctional deficits in human and murine forms of CNS lupus.