Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice

Abstract

The autoimmune-prone MRL-lpr substrain of mice develop an autoimmunity-associated behavioral syndrome (AABS) which resembles in many respects the behavior of animals exposed to chronic stress. The present study examined whether these mice show changes in the morphology of neuronal dendrites, as found in animals exposed to chronic stress. A modified Golgi–Cox procedure was used to visualize the dendrites of pyramidal neurons in the parietal cortex and in the CA1 hippocampal field of 5-week and 14-week old MRL-lpr mice and MRL +/+ controls. Reduced dendritic branching and length, and an up to 20% loss of dendritic spines were observed in parietal and hippocampal pyramidal neurons of MRL-lpr mice at both ages. In the parietal cortex, there was an age-dependent potentiation in the reduction of basilar, but not apical, dendrite branching and length, as well as in the loss of spines on basilar segments. Loss of spines in the hippocampus followed an age-related course for apical but not basilar dendrites. Moreover, compared to age-matched controls, brain weight was smaller in MRL-lpr mice at 14 but not 5 weeks of age. Considering that dendritic atrophy becomes more extensive when autoimmune disease is florid in MRL-lpr mice, it is proposed that immune/inflammatory factor(s) produce dendritic loss. Reduced dendritic complexity may represent, at least in part, a structural basis for the altered behavioral profile of MRL-lpr mice.

Introduction

The hallmark phenomena in inbred MRL/MpJ-lpr (MRL-lpr) and MRL/MpJ +/+ (MRL +/+) murine substrains are hypermaturity, accelerated aging and spontaneous development of a systemic, lupus-like autoimmune disease (Smith and Steinberg, 1983). Although MRL-lpr and MRL +/+ mice are similar in many respects (e.g., appearance, size and reproductive age), they differ in the age of onset of autoimmunity. MRL-lpr mice show lupus-like symptoms between the 2nd and the 3rd month of life whereas MRL +/+ mice show them several months later (reviewed in the work of Theofilopoulos (1992)). The principal factor accounting for the accelerated autoimmunity in the MRL-lpr substrain is a defect in Fas gene expression, produced by a point mutation in the lpr gene on chromosome 19 (reviewed in the work of Shirai and Klinman (1994)). This mutation interferes with normal Fas-induced apoptosis, and so contributes to prolonged survival of activated lymphocytes and autoreactive T- and B-cell clones.

Coincident with the appearance of serological indices of autoimmunity MRL-lpr mice develop a characteristic behavioral syndrome, which we labeled `autoimmunity-associated behavioral syndrome' (AABS), a constellation of behavioral alterations found in the MRL-lpr, in contrast to the MRL +/+, substrain (Šakić et al., 1997b). This syndrome in MRL-lpr mice resembles behavioral changes induced by chronic, inescapable stress (reviewed in the work of Anisman and Zacharko (1990)), as reflected by diminished exploration of novel objects and space, excessive floating in the forced swim test, reduced responsiveness to sucrose, perseveration on reversal learning, poor active avoidance learning, reduced aggressiveness, and increased `anxiety' (reviewed in the work of Šakić et al. (1997b) and Szechtman et al. (1997)). Most of the behavioral symptoms appear before overt signs of autoimmune disease, such as generalized lymphadenopathy, dermatitis, joint pathology, or glomerulonephritis. Some behavioral symptoms can be prevented by early immunosuppressive treatment with cyclophosphamide (Šakić et al., 1995Šakić et al., 1996), supporting the suggestion that autoimmune/inflammatory factors induce AABS.

Attempts to identify changes in brain morphology related to AABS failed to identify either cerebral vasculopathic or ischemic lesions in MRL-lpr mice (Hess et al., 1993), as might be expected on the basis of neuropathologic studies of human neuropsychiatric lupus (Johnson and Richardson, 1968; Ellis and Verity, 1979), or the cortical ectopias, as observed in other autoimmune strains (Sherman et al., 1987, Sherman et al., 1988, Sherman et al., 1990). About 50% of MRL-lpr mice posses enlarged ventricles (Denenberg et al., 1992), but it is not known whether this is also characteristic of the MRL +/+ substrain. The only consistent neuropathologic finding which may account for AABS is the presence of large clusters of T- and B-cells in the choroid plexus and brain parenchyma of MRL-lpr mice (Alexander et al., 1983; Vogelweid et al., 1991; Hess et al., 1993; Farrell et al., 1997). In light of such findings, and following our notion that AABS resembles the effects of chronic stress (Šakić et al., 1992), we reasoned that structural brain changes in MRL-lpr mice would be of the kind observed after chronic stress. Neuronal dendrites are one of the most plastic structural brain elements, undergoing growth or atrophy in response to such diverse manipulations as stress (Magarinos and McEwen, 1995), learning (Comery et al., 1995), circulating hormones (Magarinos and McEwen, 1995), and lesions (Kolb et al., 1997a) Consequently, in the present study we compared dendritic morphology of diseased MRL-lpr mice and MRL +/+ controls at two ages: at 5 weeks of age, when few serologic signs of lupus disease are recognizable; and at 14 weeks of age, when the disease is florid (Šakić et al., 1993Šakić et al., 1994). We expected to see little difference between the substrains at an early age, but dendritic atrophy in MRL-lpr mice at a later age. The sensorimotor parietal cortex and the CA1 field of the hippocampus were chosen for this analysis because behavior-related dendritic changes in these areas had been observed previously (Lolova, 1989; Kolb and Gibb, 1991).