Hyperactivity and attention deficits in mice with decreased levels of stress inducible phosphoprotein 1 (STIP1)

Abstract

Stress-inducible phosphoprotein I (STIP1, STI1, or HOP) is a cochaperone intermediating Hsp70/Hsp90 exchange of client proteins, but it can also be secreted to trigger prion protein-mediated neuronal signaling. Some mothers of children with autism-spectrum disorders (ASD) present antibodies against certain brain proteins, including antibodies against STIP1. Maternal antibodies can cross the fetus blood brain barrier during pregnancy, suggesting the possibility that they can interfere with STIP1 levels and presumably functions. However, it is currently unknown whether abnormal levels of STIP1 have any impact in ASD-related behavior. Here we used mice with reduced (50%) or increased STIP1 levels (5-fold) to test for potential ASD-like phenotypes. We find that increased STIP1 regulates the abundance of Hsp70 and Hsp90, whereas reduced STIP1 does not affect Hsp70, Hsp90 or the prion protein. Interestingly, BAC transgenic mice presenting 5-fold more STIP1 have no major phenotype when examined in a series of behavioral tasks, including locomotor activity, elevated plus maze, Morris water maze and 5-choice serial reaction time task (5-CSRTT). In contrast, mice with reduced STIP1 levels are hyperactive and have attentional deficits on the 5-CSRTT, but have normal performance in the other tasks. We conclude that reduced STIP1 levels can contribute with phenotypes related to ASD. However, future experiments are needed to define whether it is decreased chaperone capacity or impaired prion protein signaling that contributes to these phenotypes.