Depression is an early disease manifestation in lupus-prone MRL/lpr mice
Introduction
Systemic Lupus Erythematosus (SLE) is an autoimmune disease affecting multiple organ systems, including the heart, skin, joints, and kidney. In addition, approximately 70% of lupus patients suffer central nervous system (CNS) manifestations including cognitive dysfunction and mood disorders (Bluestein, 1992), with major depression being one of the most common psychiatric presentations (as high as 40%). However, it is unclear if the neuropsychiatric signs and symptoms are secondary manifestations of widespread organ dysfunction, or if the CNS itself is a primary target of autoimmune dysfunction in lupus. Some studies suggest that the neurological manifestations in lupus may be a secondary consequence of lupus nephritis, due to uremia or inflammatory changes and increased permeability of the brain-blood-barrier (BBB). Alternatively, although lupus neuropathology can include neuronal death (Kowal et al., 2004) and loss of brain volume, behavioral abnormalities may also be evident when there is no gross CNS pathology (Hermosillo-Romo and Brey, 2002), suggesting that chemokines, autoantibodies and other inflammatory mediators may be instrumental in the pathogenesis of the neuropsychiatric manifestations of lupus (Fragoso-Loyo et al., 2007). Furthermore, it has been reported that the mood and cognitive deficits prevalent in lupus patients may not reliably correlate with measures of active disease and/or disease flares involving other organ systems (Hermosillo-Romo and Brey, 2002), suggesting primary CNS involvement in this disease. Thus, behavioral outcomes, such as depression, may represent a sensitive measure of underlying CNS disease mechanisms that have yet to be elucidated.
The diagnostic criteria for lupus include high titers of anti-nuclear autoantibodies (ANA), especially anti-double stranded (ds) DNA antibodies, which are particularly important in the pathogenesis of lupus nephritis (Deocharan et al., 2002, Putterman, 2004). In addition, autoantibodies to neuronal and/or other CNS antigens are also typically present, including N-methyl-D-aspartate receptors (NMDAR). SLE autoantibodies can damage neurons and cause cognitive deficits when the blood brain barrier is breached (Kowal et al., 2004), as can occur as a consequence of lupus related nephritis. Moreover, high immunoglobulin G (IgG) and albumin levels are present in cerebrospinal fluids in murine models of lupus, and these are cytotoxic to neurons in vitro (Sidor et al., 2005). However, it remains unclear whether the CNS lupus syndromes are directly caused by neurocytoxicity induced by high titers of autoantibodies, since immunoglobulins can not cross the intact blood brain barrier in normal individuals.
There are several lupus-prone mouse strains in current use, including MRL/lpr, NZB/W F1, and BxSB (Sakic et al., 1997b). Among the listed strains, MRL/lpr mice have been most extensively used in lupus related neuropsychiatric studies. In MRL/lpr mice, an insertion of a retrotransposon in the gene for Fas (CD95) results in defective apoptosis of lymphocytes and massive lymphoproliferation, resulting in impaired regulation of autoreactive B cells and high autoantibody titers (Chu et al., 1993). Previous studies in MRL/lpr mice have indicated numerous characteristics validating the model, such as a higher prevalence in females, increased ANA titers, and severe kidney pathology (Theofilopoulos, 1992). Moreover, emotional and cognitive deficits present in human lupus such as depression and impaired memory have been demonstrated in older male MRL/lpr mice (12–16 weeks of age) (Sakic et al., 1994), although female mice have not been systematically studied.
Lupus becomes manifest earlier, and is notably more severe, in females as compared to males in human patients as well as in most murine models of the disease, including MRL/lpr mice. Therefore, we hypothesized that neuropsychiatric manifestations would be present even earlier in female than in male mice. Thus, we decided to investigate the age of onset and severity of cognitive and affective outcomes in female MRL/lpr mice, and explore a possible relationship of neuropsychiatric manifestations to several categories of autoantibodies. To this end, we conducted a behavioral battery including tests of depression (forced swim), anxiety (elevated plus maze), sickness behavior (social preference), locomotor activity (open field), motor coordination (balance beam), and cognition (novel object recognition test). Finally, we investigated neuropathology in this lupus-prone strain by magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI).
Section snippets
Mice
Ten 3–4 week old MRL/MpJ-Faslpr (MRL/lpr; stock #006825) female mice and 10 age and background matched MRL/MpJ (MRL/+; stock #000486) female mice were purchased from The Jackson Laboratory (Bar Harbor, Maine), and housed five mice per cage in the animal facility of the Albert Einstein College of Medicine (Bronx, NY). The housing conditions were controlled, with the temperature at 21–23 °C and a 12:12 h light:dark cycle. All animal studies were approved by the Institutional Animal Care and Use
Lupus-prone MRL/lpr mice develop higher autoantibody titers by 8 weeks of age
The onset and severity of murine lupus is usually measured by autoantibody levels, especially titers of anti-dsDNA and other autoantibodies, and the amount of urinary protein excretion (proteinuria), which reflects kidney dysfunction. We monitored these parameters in lupus-prone MRL/lpr female mice and the congenic wild type control MRL/+ mice over the time-course of the study, starting from 6 weeks to the mid-disease point at 18 weeks of age.
We found that typical serologic indicators of lupus
Discussion
Major depression is one of the most common neuropsychiatric manifestations in SLE patients (Wekking, 1993). In our study, female MRL/lpr mice showed depressive behavior as early as 8 weeks of age, the onset of the lupus-like disease. This significant increase in behavioral despair in the forced swim test was not accompanied by abnormal behavior in tests of general activity, motor activity, anxiety, social activity and visual memory. Excessive floating and early cessation of attempts to escape
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