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

Author(s):Show less -

Beraldo, Flavio H. ^[1] ; Thomas, Anu ^[1] ; Kolisnyk, Benjamin ^{[1, 2]} ; Hirata, Pedro H. ^[1] ; De Jaeger, Xavier ^[1] ; Martyn, Amanda C. ^[1] ; Fan, Jue ^[1] ; Goncalves, Daniela F. ^[1] ; Cowan, Matthew F. ^[1] ; Masood, Talal ^{[1, 2]} ; Martins, Vilma R. ^{[3, 4]} ; Gros, Robert ^{[1, 5]} ; Prado, Vania F. ^{[1, 2, 5, 6]} ; Prado, Marco A. M. ^{[1, 2, 5, 6]}

Affiliation

^[1] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5B7 - Canada

^[2] Univ Western Ontario, Program Neurosci, London, ON N6A 5B7 - Canada

^[3] AC Camargo Canc Ctr, Int Res Ctr, Dept Mol & Cell Biol, BR-01508010 Sao Paulo, SP - Brazil

^[4] Natl Inst Translat, Neurosci Res Ctr, BR-01508010 Sao Paulo, SP - Brazil

^[5] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5B7 - Canada

^[6] Univ Western Ontario, Dept Anat & Cell Biol, London, ON N6A 5B7 - Canada

• Document type: Journal article
• Source: Disease Models & Mechanisms; v. 8, n. 11, p. 1457-1466, NOV 2015.
• Web of Science Citations: 7

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 (fivefold) to test for potential ASD-like phenotypes. We found 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 fivefold more STIP1 show no major phenotype when examined in a series of behavioral tasks, including locomotor activity, elevated plus maze, Morris water maze and five-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 exhibit normal performance for the other tasks. We conclude that reduced STIP1 levels can contribute to 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. (AU)

• FAPESP's process: 09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches
• Grantee: Vilma Regina Martins
• Support Opportunities: Research Projects - Thematic Grants