Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex

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 (130 Hz; 200 mu A; 90 mu s)in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca2+/calmodulin-dependent protein kinase (CaMKII alpha/beta, glycogen synthase kinase 3 (GSKI alpha/beta) 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; 100 mu g/day, 14 days, 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 CaMKII alpha/beta and GSK3 alpha/beta significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKII alpha/beta, GSK3 alpha/beta, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKII alpha/beta, and GSK3 alpha/beta in the LHb together with the downregulation of CaMKII alpha/beta, GSK3 alpha/beta, and AMPI( in the IL, contribute to the antidepressant actions of DBS. (C) 2016 Elsevier B.V. All rights reserved.