title: A role for synapsin in FKBP51 modulation of stress responsiveness: Convergent evidence from animal and human studies.
abstract: Both the molecular co-chaperone FKBP51 and the presynaptic vesicle protein synapsin (alternatively spliced from SYN1-3) are intensively discussed players in the still insufficiently explored pathobiology of psychiatric disorders such as major depression, schizophrenia and posttraumatic stress disorder (PTSD). To address their still unknown interaction, we compared the expression levels of synapsin and five other neurostructural and HPA axis related marker proteins in the prefrontal cortex (PFC) and the hippocampus of restrained-stressed and unstressed Fkbp5 knockout mice and corresponding wild-type littermates. In addition, we compared and correlated the gene expression levels of SYN1, SYN2 and FKBP5 in three different online datasets comprising expression data of human healthy subjects as well as of predominantly medicated patients with different psychiatric disorders. In summary, we found that Fkbp5 deletion, which we previously demonstrated to improve stress-coping behavior in mice, prevents the stress-induced decline in prefrontal cortical (pc), but not in hippocampal synapsin expression. Accordingly, pc, but not hippocampal, synapsin protein levels correlated positively with a more active mouse stress coping behavior. Searching for an underlying mechanism, we found evidence that deletion of Fkbp5 might prevent stress-induced pc synapsin loss, at least in part, through improvement of pc Akt kinase activity. These results, together with our finding that FKBP5 and SYN1 mRNA levels were regulated in opposite directions in the PFC of schizophrenic patients, who are known for exhibiting an altered stress-coping behavior, provide the first evidence of a role for pc synapsin in FKBP51 modulation of stress responsiveness. This role might extend to other tissues, as we found FKBP5 and SYN1 levels to correlate inversely not only in human PFC samples but also in other expression sites. The main limitation of this study is the small number of individuals included in the correlation analyses. Future studies will have to verify the here-postulated role of the FKBP51-Akt kinase-synapsin pathway in stress responsiveness.
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany. Electronic address: uschmidt@mpipsykl.mpg.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Buell
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Ionescu
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Germany.
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968, United States.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
authors.forename: Bozidar
authors.initials: B
authors.lastname: Novak
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Huber
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute of Psychiatry, Department of Stress Neurobiology and Neurogenetics, Germany.
authors.forename: Chadi
authors.initials: C
authors.lastname: Touma
authors.affiliation: Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Germany.
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.affiliation: Max Planck Institute of Psychiatry, Department of Clinical Research, RG Molecular Psychotraumatology, Munich, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Herrmann
mesh_terms: D000223:Adaptation, Psychological / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D001523:Mental Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger; D013315:Stress, Psychological / Q000378:metabolism*; D016704:Synapsins / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D012333:RNA, Messenger; D016704:Synapsins; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Akt kinase; Bipolar disorder; FKBP5 knockout mice; FKBP51; HPA axis; PTSD; Prefrontal cortex; Schizophrenia; Stress reactivity; Synapsin