title: Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex.
abstract: High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200μA; 90μs) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKIIα/β), glycogen synthase kinase 3 (GSK3α/β) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100μg/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKIIα/β and GSK3α/β significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKIIα/β, GSK3α/β, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKIIα/β, and GSK3α/β in the LHb together with the downregulation of CaMKIIα/β, GSK3α/β, and AMPK in the IL, contribute to the antidepressant actions of DBS.
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA; School of Psychology, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Yesul
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Morath
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.affiliation: School of Psychology, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Byrne
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Shari L
authors.initials: SL
authors.lastname: Sutor
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA; School of Psychology, Deakin University, Burwood, Victoria 3125, Australia; Department of Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: tye.susannah@mayo.edu.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Tye
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000627:therapeutic use; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D046690:Deep Brain Stimulation / Q000379:methods*; D061218:Depressive Disorder, Treatment-Resistant / Q000628:therapy*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D019262:Habenula / Q000502:physiology*; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D065726:Limbic Lobe / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013550:Swimming / Q000523:psychology
chemical_list: D000324:Adrenocorticotropic Hormone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases
keywords: AMPK; CaMKII; Deep brain stimulation; GSK3; Lateral habenula; Treatment resistant depression