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Background   PTEN , a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between  PTEN  and ASD and ensuing studies, we continue to have a limited understanding of how  PTEN  disruption drives ASD pathogenesis and maintenance.    Methods  We derived neural stem cells (NSCs) from the dentate gyrus (DG) of  Pten   m3m4   mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in  Pten   m3m4   NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR.    Results  The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time.  Pten   m3m4   NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of  Pten   m3m4   NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some  Pten   m3m4   glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in  Pten   m3m4/m3m4   NSCs. We specifically observed loss of Creb phosphorylation at S133 in  Pten   m3m4/m3m4   NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in  Pten   m3m4/m3m4   NSCs.    Conclusions  Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis.    Graphical abstract

Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation