title: Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption.
abstract: Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSEor highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSEfollowed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior.
authors.affiliation: Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Gottschalk
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Psychology, Emmanuel College, Boston, MA, USA.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Leussis
authors.affiliation: Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK; Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Ruland
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Klaudio
authors.initials: K
authors.lastname: Gjeluci
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Electronic address: tpetryshen@mgh.harvard.edu.
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Petryshen
authors.affiliation: Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK. Electronic address: sb209@cam.ac.uk.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bahn
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000172:deficiency / Q000235:genetics*; D018692:Antimanic Agents / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D001370:Axonal Transport / Q000187:drug effects*; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D018020:Lithium Compounds / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D001523:Mental Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053719:Tandem Mass Spectrometry
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D018692:Antimanic Agents; D018020:Lithium Compounds; D018698:Glutamic Acid
keywords: Bipolar disorder; Mass spectrometry; Protein interaction networks; Proteomics; Translational model