PMID- 26519901 OWN - NLM STAT- MEDLINE DCOM- 20161007 LR - 20220419 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 102 DP - 2016 Mar TI - BDNF - a key transducer of antidepressant effects. PG - 72-9 LID - S0028-3908(15)30157-X [pii] LID - 10.1016/j.neuropharm.2015.10.034 [doi] AB - How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Bjorkholm, Carl AU - Bjorkholm C AD - Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. FAU - Monteggia, Lisa M AU - Monteggia LM AD - Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: lisa.monteggia@utsouthwestern.edu. LA - eng GR - R01 MH070727/MH/NIMH NIH HHS/United States GR - MH070727/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20151111 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) SB - IM MH - Animals MH - Antidepressive Agents/pharmacology/*therapeutic use MH - Brain-Derived Neurotrophic Factor/metabolism/pharmacology/*therapeutic use MH - Depression/drug therapy/*metabolism MH - Disease Models, Animal MH - Hippocampus/drug effects/metabolism MH - Humans MH - Mice PMC - PMC4763983 MID - NIHMS737576 OTO - NOTNLM OT - Behavior OT - Brain-derived neurotrophic factor OT - Depression OT - Hippocampus OT - Synaptic plasticity EDAT- 2015/11/01 06:00 MHDA- 2016/10/08 06:00 PMCR- 2017/03/01 CRDT- 2015/11/01 06:00 PHST- 2015/08/21 00:00 [received] PHST- 2015/10/13 00:00 [revised] PHST- 2015/10/25 00:00 [accepted] PHST- 2017/03/01 00:00 [pmc-release] PHST- 2015/11/01 06:00 [entrez] PHST- 2015/11/01 06:00 [pubmed] PHST- 2016/10/08 06:00 [medline] AID - S0028-3908(15)30157-X [pii] AID - 10.1016/j.neuropharm.2015.10.034 [doi] PST - ppublish SO - Neuropharmacology. 2016 Mar;102:72-9. doi: 10.1016/j.neuropharm.2015.10.034. Epub 2015 Nov 11.