title: Behavioral effects of SQSTM1/p62 overexpression in mice: support for a mitochondrial role in depression and anxiety.
abstract: Affective spectrum and anxiety disorders have come to be recognized as the most prevalently diagnosed psychiatric disorders. Among a suite of potential causes, changes in mitochondrial energy metabolism and function have been associated with such disorders. Thus, proteins that specifically change mitochondrial functionality could be identified as molecular targets for drugs related to treatment for affective spectrum disorders. Here, we report generation of transgenic mice overexpressing the scaffolding and mitophagy related protein Sequestosome1 (SQSTM1/p62) or a single point mutant (P392L) in the UBA domain of SQSTM1/p62. We show that overexpression of SQSTM1/p62 increases mitochondrial energy output and improves transcription factor import into the mitochondrial matrix. These elevated levels of mitochondrial functionality correlate directly with discernible improvements in mouse behaviors related to affective spectrum and anxiety disorders. We also describe how overexpression of SQSTM1/p62 improves spatial learning and long term memory formation in these transgenic mice. These results suggest that SQSTM1/p62 provides an attractive target for therapeutic agents potentially suitable for the treatment of anxiety and affective spectrum disorders.
authors.affiliation: Dept. Biological Sciences, Auburn University, 331 Funchess Hall, Auburn, AL 36832, USA. seibemi@auburn.ed
authors.forename: M Lamar
authors.initials: ML
authors.lastname: Seibenhener
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Du
authors.forename: Luis
authors.initials: L
authors.lastname: Calderilla-Barbosa
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.forename: Marie W
authors.initials: MW
authors.lastname: Wooten
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wooten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology; D003863:Depression / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490981:Gtf2h1 protein, mouse; D014157:Transcription Factors; D051758:Transcription Factor TFIIH