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
View: Text | PDF
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

×

Figure 3

Reduction in neuroblast chains in the tEAE SVZ.

Options: View larger image (or click on image) Download as PowerPoint
Reduction in neuroblast chains in the tEAE SVZ. (A) Numerous DCX+ cells ...
(A) Numerous DCX+ cells are present in the control subependymal area. (B) SVZ areas free of DCX+ cells with chains emigrating into the neighboring striatum (arrowheads) along the blood vessels in tEAE tissue 3 days p.i. (C and D) SVZ in tEAE mice sacrificed 2 months p.i. (C) Areas containing few DCX+ cells alter with those containing bulks of DCX+ cells as shown in D. Arrowheads in D show individual DCX+ cells in the striatum near the SVZ. SVZ limits are indicated by white dashed lines. (E) Quantification of DCX immunoreactivity in the SVZ (n = 3–6 mice/group). Decreases compared with the controls are significant in tEAE mice at 3 days and 2 months p.i. (***P = 0.0002 and **P = 0.0087, respectively), but no significant changes in the amount of DCX were observed in non-immunized mice sacrificed 3 days following cytokine injection as compared with the controls. Error bars represent SEM. (f–h) RMS in control versus tEAE mice. (F) Organized chain migration toward OB in control RMS. (G) Accumulation of DCX+ cells within the RMS region proximal to the SVZ and emigration into the corpus callosum at 7 days p.i. (arrowheads). (H) Interruptions of the RMS and individual DCX+ cells in tEAE corpus callosum, 2 months p.i. (arrowheads). Scale bars: 50 μm.