Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis
Vanja Tepavčević, Françoise Lazarini, Clara Alfaro-Cervello, Christophe Kerninon, Kazuaki Yoshikawa, José Manuel Garcia-Verdugo, Pierre-Marie Lledo, Brahim Nait-Oumesmar, Anne Baron-Van Evercooren
Vanja Tepavčević, Françoise Lazarini, Clara Alfaro-Cervello, Christophe Kerninon, Kazuaki Yoshikawa, José Manuel Garcia-Verdugo, Pierre-Marie Lledo, Brahim Nait-Oumesmar, Anne Baron-Van Evercooren
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Research Article Neuroscience

Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis

Abstract

Neural stem cells (NSCs) persist in defined brain niches, including the subventricular zone (SVZ), throughout adulthood and generate new neurons destined to support specific neurological functions. Whether brain diseases such as multiple sclerosis (MS) are associated with changes in adult NSCs and whether this might contribute to the development and/or persistence of neurological deficits remains poorly investigated. We examined SVZ function in mice in which we targeted an MS-like pathology to the forebrain. In these mice, which we refer to herein as targeted EAE (tEAE) mice, there was a reduction in the number of neuroblasts compared with control mice. Altered expression of the transcription factors Olig2 and Dlx2 in the tEAE SVZ niche was associated with amplification of pro-oligodendrogenic transit-amplifying cells and decreased neuroblast generation, which resulted in persistent reduction in olfactory bulb neurogenesis. Altered SVZ neurogenesis led to impaired long-term olfactory memory, mimicking the olfactory dysfunction observed in MS patients. Importantly, we also found that neurogenesis was reduced in the SVZ of MS patients compared with controls. Thus, our findings suggest that neuroinflammation induces functional alteration of adult NSCs that may contribute to olfactory dysfunction in MS patients.

Authors

Vanja Tepavčević, Françoise Lazarini, Clara Alfaro-Cervello, Christophe Kerninon, Kazuaki Yoshikawa, José Manuel Garcia-Verdugo, Pierre-Marie Lledo, Brahim Nait-Oumesmar, Anne Baron-Van Evercooren

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Figure 4

Analysis of SVZ ultrastructure during tEAE.

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Analysis of SVZ ultrastructure during tEAE. (A–D) Schematic representati...
(A–D) Schematic representation of SVZ organization, with each cell type shown in different color. Neuroblasts are shown in red. Reduction in red cells is obvious at 3 days p.i. in tEAE mice. Some recovery occurs at later time points, but control levels are not reached. Images are illustrations of the boxed areas within each schematic representation. (A) Chain of migrating neuroblasts (A) surrounded by astrocytes (B) in the control SVZ. (B) Macrophages (M) and pyknotic cell (P) next to blood vessels within tEAE SVZ 3 days p.i. (C) Upper panel: Large astrocytes (B) next to small neuroblast chain (A); lower panel: type C cells in tEAE SVZ 7 days p.i. (D) Astrocyte (B) processes and small myelinated axons (arrowheads) separate neuroblasts (A) and some C cells (C) from the ependyma in tEAE SVZ 1 month p.i. (E) Quantification of A cells in the SVZ of control and tEAE mice. **P = 0.002, *P = 0.01, †P = 0.005 versus control; n = 3–4 mice/group; error bars represent SEM. (F) SVZ composition represented as average percentages of each cell type within total SVZ cells (3–4 mice/group). While in the control, SVZ neuroblasts (red) predominate, their reduction is obvious during tEAE. The pathology, however, progressively increases type C cells (green). Astrocytes contacting the lateral ventricle are presented in white and non-identified cells in light blue.