title: 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 co-chaperone 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.
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada fberaldo@robarts.ca vprado@robarts.ca mprado@robarts.ca.
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Anu
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada Program in Neuroscience, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kolisnyk
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Pedro H
authors.initials: PH
authors.lastname: Hirata
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: De Jaeger
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Martyn
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Jue
authors.initials: J
authors.lastname: Fan
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Goncalves
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Cowan
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada Program in Neuroscience, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Talal
authors.initials: T
authors.lastname: Masood
authors.affiliation: Department of Molecular and Cell Biology, International Research Center, A.C. Camargo Cancer Center and National Institute for Translational Neuroscience Research Center, Sao Paulo, SP 01508-010, Brazil.
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A5B7, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada Program in Neuroscience, The University of Western Ontario, London, Ontario N6A5B7, Canada Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A5B7, Canada Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A5B7, Canada fberaldo@robarts.ca vprado@robarts.ca mprado@robarts.ca.
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario N6A5B7, Canada Program in Neuroscience, The University of Western Ontario, London, Ontario N6A5B7, Canada Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A5B7, Canada Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A5B7, Canada fberaldo@robarts.ca vprado@robarts.ca mprado@robarts.ca.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D001522:Behavior, Animal; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D010641:Phenotype; D018621:PrPC Proteins / Q000378:metabolism; D011930:Reaction Time; D013550:Swimming; D013997:Time Factors
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018621:PrPC Proteins; C489791:Stip1 protein, mouse
keywords: ASD; Attention deficits; Autism; BAC; Mouse model; Stress-inducible phosphoprotein 1; Touchscreen