Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis
Vanja Tepavčević, … , Brahim Nait-Oumesmar, Anne Baron-Van Evercooren
Vanja Tepavčević, … , Brahim Nait-Oumesmar, Anne Baron-Van Evercooren
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4722-4734. https://doi.org/10.1172/JCI59145.
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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 2

SVZ inflammation correlates with modulation of proliferation in tEAE mice in a time-dependent manner.

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SVZ inflammation correlates with modulation of proliferation in tEAE mic...
(A–D) IHC for CD45 in the SVZ. (A) Absence of strongly labeled cells in the SVZ of control mice. (B) Cytokine injection into non-immunized mice leads to a moderate increase in hematopoietic cell numbers in the SVZ 3 days p.i. (cyt 3d). (C) Extensive increase in numbers of inflammatory cells during the first week p.i. occurs in MOG peptide–immunized mice (tEAE 3d). (D) Numbers of inflammatory cells decrease in tEAE mice sacrificed at 2 months p.i. (tEAE 2m) compared with early phases but do not reach control levels. (E) Quantification of CD45+ cells in the SVZ (n = 3–4 mice/group; *P = 0.04, †P = 0.01, ‡P = 0.02, §P = 0.01, P = 0.04). (F–I) IHC for BrdU in the SVZ. (F) Control SVZ. (G) Decrease in BrdU+ cell numbers in tEAE SVZ 3 days p.i., while proliferation is upregulated in the neighboring parenchyma. (H) Increase in BrdU+ cell numbers in the SVZ at 7 days p.i. (I) Recovery of basal levels 2 months p.i. (J) Quantification of BrdU+ cells in the SVZ (n = 5–7 mice/group; **P = 0.0026, #P = 0.004 versus control). Error bars represent SEM. Scale bars: 50 μm.