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

J Clin Invest. 2011 Dec;121(12):4722-34. doi: 10.1172/JCI59145. Epub 2011 Nov 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / physiology*
  • Animals
  • Astrocytes / pathology
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Lineage
  • Corpus Callosum / pathology
  • Disease Models, Animal*
  • Encephalomyelitis, Autoimmune, Experimental / complications
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology*
  • Gene Expression Regulation
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics
  • Humans
  • Interneurons / pathology
  • Lateral Ventricles / physiopathology*
  • Memory, Long-Term / physiology
  • Mice
  • Multiple Sclerosis*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Neural Stem Cells / pathology*
  • Neurogenesis / genetics
  • Olfaction Disorders / etiology*
  • Olfaction Disorders / pathology
  • Olfactory Bulb / pathology*
  • Oligodendrocyte Transcription Factor 2
  • Oligodendroglia / pathology
  • Stem Cell Niche / physiology*
  • Transcription Factors / biosynthesis
  • Transcription Factors / deficiency
  • Transcription Factors / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Distal-less homeobox proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Transcription Factors