Hippocampal damage in mouse and human forms of systemic autoimmune disease

Abstract

Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJBpositive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

“…A more detailed pathological analysis of the brain from the NP-SLE patient has been reported elsewhere (Ballok et al, 2004b). In brief, routine neuropathological analysis revealed dilatation of the third and lateral ventricles and thinning of surrounding cortex.…”

Neuroimmunopathology in a murine model of neuropsychiatric lupus

“…A small percentage of these neurons where subsequently found to contain TdTlabeled apoptotic nuclei, and co-localized with FJB (Ballok et al, 2003) and anti-neurofilament staining (Alexander et al, 2005a). Providing further evidence of neurodegeneration, while the size of hippocampal fields and neuronal density are not reduced in young Fas-deficient lpr mice (Kovac et al, 2002), cell densities are reduced within the hippocampus, cortex (Ballok et al, 2004b) and midbrain (Ballok et al, 2004a) of aged/diseased lupus mice.…”

“…An impairment in this process would likely exacerbate subsequent autoimmune/inflammatorymediated neuronal death and behavioral deficits. For example, an impaired capacity for hippocampal neurogenesis could account for the cognitive impairments observed in these animals (Ballok et al, 2004b). Stress hormones, chronically elevated in lupus mice (Lechner et al, 2000), have also been shown to inhibit cell proliferation and neurogenesis (Mirescu and Gould, 2006), and may additionally account for impaired brain growth and regeneration along the progression of autoimmune disease.…”

“…The nature of this autoimmune-associated behavioral syndrome (AABS) suggests a progressive anxious-and depressive-like state (and differences in emotionality), as indicated by increased thigmotaxic behavior, impaired exploration of novel objects and spaces, performance deficits in the plus-maze and step-down tests, excessive floating in the forced swim test (FST) (Sakic et al, 1992(Sakic et al, , 1993a(Sakic et al, , 1994, reduced responsiveness to a palatable stimulus (Sakic et al, 1996a), and reduced isolation-induced inter-male fighting (Sakic et al, 1998a). Moreover, impaired "cognitive flexibility" and poor spatial learning was revealed through the Morris water maze (Sakic et al, 1993b), and spontaneous alternation behavioral test (Ballok et al, 2004b). In addition, diseased MRL-lpr animals display lower nocturnal and open-field activity, and significant deficiencies in neurological (Hess et al, 1993;Brey et al, 1997b) and psychomotor (beam-walking) tests (Sakic et al, 1993a(Sakic et al, , 1996b.…”

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

“…Comparable to brain lesions and loss of brain volume in CNS-SLE, 11 a significant proportion of MRL-lpr mice show ventricular enlargement, 12 reduced brain mass, autoimmunity-associated atrophy of neuronal dendrites 13,14 and bona fide neuronal degeneration. 15,16 At the onset of SLE-like disease, MRL-lpr mice show a constellation of deficits in emotional reactivity and motivated behavior, operationally defined as 'autoimmunityassociated behavioral syndrome' or AABS. 9 Based on documented role of central monoamines in control of mood and motivation, 17 our recent studies are aimed at examining neurotransmitter perturbations associated with various aspects of AABS.…”