Neural Stem Cells from Shank3-ko Mouse Model Autism Spectrum Disorders.

ABSTRACT

Autism spectrum disorders (ASD) comprise a complex of neurodevelopmental disorders caused by a variety of genetic defects and characterized by alterations in social communication and repetitive behavior. Since the mechanisms leading to early neuronal degeneration remain elusive, we chose to examine the properties of NSCs isolated from an animal model of ASD in order to evaluate whether their neurogenic potential may recapitulate the early phases of neurogenesis in the brain of ASD patients. Mutations of the gene coding for the Shank3 protein play a key role in the impairment of brain development and synaptogenesis in ASD patients. Experiments here reported show that NSCs derived from the subventricular zone (SVZ) of adult Shank3Δ11-/- (Shank3-ko) mice retain self-renewal capacity in vitro, but differentiate earlier than wild-type (wt) cells, displaying an evident endosomal/lysosomal and ubiquitin aggregation in astroglial cells together with mitochondrial impairment and inflammasome activation, suggesting that glial degeneration likely contributes to neuronal damage in ASD. These in vitro observations obtained in our disease model are consistent with data in vivo obtained in ASD patients and suggest that Shank3 deficit could affect the late phases of neurogenesis and/or the survival of mature cells rather than NSC self-renewal. This evidence supports Shank3-ko NSCs as a reliable in vitro disease model and suggests the rescue of glial cells as a therapeutic strategy to prevent neuronal degeneration in ASD.