Long‐term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis

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Multiple sclerosis (MS) is an autoimmune demyelinating disorder affecting the central nervous system (CNS), is commonly diagnosed in the prime of life, and in most cases leads to chronic disability (Noseworthy et al., 2000). Gray matter brain structures, including deep nuclei and the cerebral cortex, are affected significantly and early in the course of MS, and these changes may not be directly related to demyelinating white matter (Sicotte et al., 2008). Although other gray matter regions have been studied, relatively little is known of the extent of hippocampal involvement in MS. Impaired cognitive function is present in 25% to 60% of patients with MS (Rao et al., 1991), can occur in the setting of relatively mild physical disability, and is detectable even before a definitive diagnosis of MS is made (Achiron and Barak, 2003). The most frequently detected cognitive deficits in MS are noted in information‐processing speed and working memory; however, verbal and spatial learning are also affected, possibly reflecting hippocampal dysfunction (Thornton and Raz, 1997; Thornton et al., 2002). Evidence of hippocampal atrophy in MS has been reported in recent histopathologic studies (Geurts et al., 2007; Papadopoulos et al., 2009) and in MRI studies; moreover, this volume loss was in excess of global brain atrophy (Geurts et al., 2006).
The hippocampus is an archicortical structure composed of several subregions with differing histology and functional specificity that plays a critical role in episodic memory formation and retrieval (Squire et al., 2004) and is especially sensitive to multiple insults including inflammation. The neurogenetic region of the adult hippocampus is the dentate gyrus (DG), where neural precursor cells (NPCs) located in the subgranular zone (SGZ), the neurogenic niche between the hilus and granule cell layer (GCL), give rise to thousands of new cells every day. Production of new dentate granule neurons is a multistep process regulated by extrinsic and local stimuli (Goldman and Chen, 2011). Interestingly, an excess is generated, but only a fraction remains to differentiate into mature functional neurons and/or astrocytes, depending on the need of the local hippocampal environment (Cameron et al., 1993; Encinas et al., 2011; Kuipers et al., 2009). These new cells differentiate into granule cells, which migrate up into the GCL, incorporate into the functional hippocampal circuitry through the establishment of synaptic contacts, and participate in spatial memory formation (Kuruba et al., 2009).
In this study we used experimental autoimmune encephalomyelitis (EAE), the most reliable, up‐to‐date experimental model of MS, to investigate the long‐term effects of CNS inflammation on hippocampal neurogenesis. Particularly, changes in absolute numbers of proliferating cells and early neuroprogenitor pool were investigated in EAE adult mice, by 5‐bromodeoxyuridine (BrdU), Ki67, and doublecortin (DCX) immunohistochemistry (IHC). Phenotypes of proliferating cells were also characterized by determining the proportion of BrdU + cells coexpressing GFAP, S100, calretinin, and NeuN across the control and EAE groups (Kempermann et al., 2004; Zhao et al., 2008).
The present study confirms others supporting that the inflammatory environment prevailing in the brain of EAE mice enhances the proliferation of NPCs and reduces the capacity of these cells to generate mature neurons (Aharoni et al., 2005; Arnon and Aharoni, 2009; Guo et al., 2010; Huehnchen et al., 2011). However, for the first time we show that EAE‐induced neuroinflammation intervenes in NPC differentiation by shifting the fate of newborn cells towards the glial cell lineage and enhancing their dispersion into the GCL. Moreover, our data suggest that although in the long term the stemness in DG is not drastically affected, there is an overall alteration in the proportions of NPC subpopulations in favor of more immature phenotypes.
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