Behavioral heterogeneity in an animal model of neuropsychiatric lupus

Šakić, Boris; Hanna, Steven; Millward, Jason M.

doi:10.1016/j.biopsych.2004.11.037

Cited by 27 publications

(31 citation statements)

References 78 publications

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“…Since onset of serological and peripheral manifestations differs among littermates, dissimilar timing in loss of central dopaminergic neurons may contribute to behavioral heterogeneity and proclivity to SIB in the inbred MRL-lpr substrain. 43 In summary, one may hypothesize that diverse behavioral deficits in MRL-lpr mice are result of complex genetic and perinatal autoimmune mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

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Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/ 3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg À1 body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL þ / þ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood.

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Section: Discussionmentioning

confidence: 99%

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

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“…The MRL-lpr strain, however, has no gender bias, possibly suggesting a different hormonal differentiation between two sexes in human and murine lupus. Lastly, while more sophisticated and systematic assessments are administered in human SLE, affective states of MRL-lpr mice can only be assessed by behavioral tests (Scolding and Joseph, 2002;Sakic et al, 2005a), and care is required when transferring information obtained from an animal model to human disease. Despite these limitations, the MRL model of NP-SLE remains a critical tool toward understanding the complex etiopathogenesis of this neuroimmunological syndrome.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Neuroimmunopathology in a murine model of neuropsychiatric lupus

Ballok

2007

Brain Research Reviews

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Animal models are extremely useful tools in defining pathogenesis and treatment of human disease. For many years researchers believed that structural damage to the brain of neuropsychiatric (NP) patients lead to abnormal mental function, but this possibility was not extensively explored until recently. Imaging studies of NP-systemic lupus erythematosus (SLE) support the notion that brain cell death accounts for the emergence of neurologic and psychiatric symptoms, and evidence suggests that it is an autoimmunity-induced brain disorder characterized by profound metabolic alterations and progressive neuronal loss. While there are a number of murine models of SLE, this article reviews recent literature on the immunological connections to neurodegeneration and behavioral dysfunction in the Fas-deficient MRL model of NP-SLE. Probable links between spontaneous peripheral immune activation, the subsequent central autoimmune/inflammatory responses in MRL/MpJ-Tnfrsf6 lpr (MRL-lpr) mice and the sequential mode of events leading to Fas-independent neurodegenerative autoimmune-induced encephalitis will be reviewed. The role of hormones, alternative mechanisms of cell death, the impact of central dopaminergic degeneration on behavior, and germinal layer lesions on developmental/regenerative capacity of MRL-lpr brains will also be explored. This model can provide direction for future therapeutic interventions in patients with this complex neuroimmunological syndrome.

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“…The observed behavioral changes are not completely dependent on the systemic pathology, since we observed behavioral alterations in these mice from 5 wk of age (data not shown), at which point they are clinically normal. Furthermore, others have reported that these mice showed heightened emotional reactivity and displayed increased anxiety and decreased exploratory behavior at an age when they are free of clinical symptoms, which could impair their ability to perform behavioral tasks [55]. These behavioral alterations could also be cytokine driven, since deposition of immune complexes could lead to changes in cytokine profiles [56].…”

Section: Behavioral Changes In Mrl/lpr Mice Are Complement Dependentmentioning

confidence: 99%

Absence of functional alternative complement pathway alleviates lupus cerebritis

et al. 2007

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The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB -/-MRL/lpr) compared to fBsufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 AE 0.02 vs. 0.35 AE 0.13, p <0.03) was increased, while expression of p-PTEN (0.40 AE 0.06 vs. 0.11 AE 0.07, p <0.05) was decreased in fB -/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB -/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis. IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease, with central nervous system (CNS) involvement occurring in 20-70% of patients. Complement activation is believed to play a key role in the pathogenesis of SLE [1]. The relevance of complement in lupus cerebritis is supported by enhanced C3 and C4 index values in the cerebrospinal fluid of patients [2] and increased levels of the anaphylatoxins, C3a and C5a, which correlate with the CNS flares [3]. This is also true in experimental lupus cerebritis, and is supported by our recent studies, in which systemic inhibition of the C3/C5 convertases reduced pathological alterations in the CNS of the lupus mouse model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice [4,5]. Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined. Bb, one of the split products of fB, can induce apoptosis [17], which is a key feature in the brains of MRL/lpr mice [5,18]. Apoptosis can also be induced by several other factors such as nitric oxide (NO), edema, and the extracellular matrix (ECM) proteins through integrin si...

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Behavioral heterogeneity in an animal model of neuropsychiatric lupus

Cited by 27 publications

References 78 publications

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Neuroimmunopathology in a murine model of neuropsychiatric lupus

Absence of functional alternative complement pathway alleviates lupus cerebritis

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