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      Abnormal increase of neuronal precursor cells and exacerbated neuroinflammation in the corpus callosum in murine model of systemic lupus erythematosus

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          Purpose: Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterised by elevated levels of autoantibodies and cytokines in the body. Via alteration of the regulation of inflammation, damage to different organ systems, including the central nervous system (CNS), was found in SLE patients. Patients diagnosed with SLE were reported to suffer from different kinds of psychiatric signs and symptoms. As neurogenesis has been suggested to be a potential key player of psychiatric symptoms and emotional behavior disturbances, this study aims to investigate whether neurogenesis is altered in an animal model of SLE. Also, neuroinflammation was studied.

          Methods: Female NZB/W F1 mice were used as an animal model of SLE. Animals were divided into two groups: 1. pre-diseased mice (lupus-prone NZB/W F1 female mice, age 10–15 weeks, negative for proteinuria and with basal levels of serum anti-dsDNA autoantibodies) and 2. diseased mice (NZB/W F1 female mice, > 25 weeks of age, with elevated serum levels of anti-dsDNA autoantibodies and with persistent proteinuria of > 3 mg/ml for more than 2 weeks). Comparisons of the levels of neurogenesis and neuroinflammtion between two groups of mice were studied by the immunohistochemistry.

          Results: After the onset of SLE symptoms, a reduction of neurogenesis in the hippocampus was found, while there was a dramatic increase of doublecortin (DCX+) neuronal precursor cells in the corpus callosum (CC) and in the subventricular zone (SVZ). Meanwhile, exacerbated inflammation was present in the corpus callosum of the diseased mice, which was suggested by the increased number of GFAP+ cells and IBA-1+ cells.

          Conclusions: To the best of our knowledge, this is the first study showing an increase of neuronal precursor cells in the corpus callosum of the female NZB/W F1 mice. The present study suggests a coincidence but not a causal relationship between neurogenesis and neuroinflammation. The present results have also provided new insight showing that the altered neurogenesis and neuroinflammation may be a potential neurological mechanism for the cognitive and mood disturbance found in the SLE patients.

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          Most cited references 42

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          A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain.

          Active adult neurogenesis occurs in discrete brain regions of all mammals and is widely regarded as a neuronal replacement mechanism. Whether adult-born neurons make unique contributions to brain functions is largely unknown. Here we systematically characterized synaptic plasticity of retrovirally labeled adult-born dentate granule cells at different stages during their neuronal maturation. We identified a critical period between 1 and 1.5 months of the cell age when adult-born neurons exhibit enhanced long-term potentiation with increased potentiation amplitude and decreased induction threshold. Furthermore, such enhanced plasticity in adult-born neurons depends on developmentally regulated synaptic expression of NR2B-containing NMDA receptors. Our study demonstrates that adult-born neurons exhibit the same classic critical period plasticity as neurons in the developing nervous system. The transient nature of such enhanced plasticity may provide a fundamental mechanism allowing adult-born neurons within the critical period to serve as major mediators of experience-induced plasticity while maintaining stability of the mature circuitry.
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            Long-distance neuronal migration in the adult mammalian brain.

            During the development of the mammalian brain, neuronal precursors migrate to their final destination from their site of birth in the ventricular and subventricular zones (VZ and SVZ, respectively). SVZ cells in the walls of the lateral ventricle continue to proliferate in the brain of adult mice and can generate neurons in vitro, but their fate in vivo is unknown. Here SVZ cells from adult mice that carry a neuronal-specific transgene were grafted into the brain of adult recipients. In addition, the fate of endogenous SVZ cells was examined by microinjection of tritiated thymidine or a vital dye that labeled a discrete population of SVZ cells. Grafted and endogenous SVZ cells in the lateral ventricle of adult mice migrate long distances and differentiate into neurons in the olfactory bulb.
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              Neurogenesis in adult subventricular zone.


                Author and article information

                Restor Neurol Neurosci
                Restor. Neurol. Neurosci
                Restorative Neurology and Neuroscience
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                2 May 2016
                14 June 2016
                : 34
                : 3
                : 443-453
                [a ]Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong , Hong Kong
                [b ]Rehabilitation Sciences, The Hong Kong Polytechnic University , Hong Kong
                [c ]Department of Ophthalmology, LKS Faculty of Medicine, The University of Hong Kong , Hong Kong
                [d ]State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong , Hong Kong
                [e ]GHM Institute of CNS Regeneration, Jinan University , Guangzhou, China
                [f ]Co-innovation Center of Neuroregeneration, Nantong University , Jiangsu, China
                [g ]Ministry of Education CNS Regeneration International Collaborative Joint Laboratory, Jinan University , Guangzhou, China
                Author notes

                Co-first authors.


                Co-corresponding authors.

                [* ]Corresponding author: Kwok-Fai So, Department of Ophthalmology, The University of Hong Kong, 5 Sassoon Road, Hong Kong. Tel.: +852 2831 5366; Fax: +852 2817 0941; E-mail: hrmaskf@ .
                IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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