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 8

Olfactory dysfunction in tEAE mice.

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Olfactory dysfunction in tEAE mice. (A) Spontaneous olfactory discrimina...
(A) Spontaneous olfactory discrimination. Histograms indicate mean time of odorant investigation within 2-minute exposure (rest intervals, 2 minutes). Eight sets of columns represent 4 habituations to heptanal (Hept), dishabituation (similar odorant, octanal [Oct]), 2 habituation recalls (Hept) and a final dishabituation (dissimilar odorant, geraniol [Ger]). ***P < 0.0001. (B) Reinforced olfactory discrimination between pairs of binary mixtures consisting of different linalool (L, rewarded odorant)/geraniol (no reward) ratios. Vertical axis represents correct response percentage for 10 blocks of 20 trials. Dashed line represents chance level (50%). (C and D) Short-term olfactory memory was tested by mint odorant presentation twice for 2 minutes (2-minute pause), followed by 30 minutes rest period and then 2-minute memory test (C). (D) Histograms indicate the mean investigation time. ***P < 0.0001. (E–I) Long-term olfactory memory. (E) Mice learned to discriminate (day 1) between 1% n-amyl acetate (rewarded odorant, S+) and 1% cineole (non-rewarded odorant, S–), which was followed by a 4-day task consolidation (days 2–5) and then a 40-day rest period. Memory was tested in 1 block of 20 trials (10 S+, 10 S–, random). (F) Mean percentages of correct responses in the training session 5 versus memory test. Chance level is represented by dashed line (50%); *P = 0.0132. (G) Mean error numbers for memory test: *P = 0.0151. (H) Mean error numbers in S+ memory trials: **P = 0.0067. (I) Mean probability of miss in S+ trials (error number in S+ trials/number of S+ trials): ***P = 0.0001. n = 7–9 mice/group. Error bars indicate SEM.