Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects.
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ABSTRACT:
SUBMITTER: Govindarajan A
PROVIDER: S-EPMC1559778 | biostudies-literature | 2006 Aug
REPOSITORIES: biostudies-literature
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Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects.
Govindarajan Arvind A Rao B S Shankaranarayana BS Nair Deepti D Trinh Mimi M Mawjee Nadya N Tonegawa Susumu S Chattarji Sumantra S
Proceedings of the National Academy of Sciences of the United States of America 20060821 35
Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signali ...[more]
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Project description:ObjectiveA model has been proposed to explain the pathophysiology of mood disorders based on decreased neurotrophin levels during mood episodes; treatment with antidepressants and mood stabilizers is associated with clinical improvement. This study investigated whether changes in brain-derived neurotrophic factor (BDNF) levels are associated with the initial antidepressant effects of ketamine, a high-affinity N-methyl-D-aspartate (NMDA) antagonist.MethodTwenty-three subjects aged 18 to 65 years with DSM-IV major depressive disorder (treatment resistant) participated in this study, which was conducted between October 2006 and May 2008. The subjects were given an open-label intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and rated using various depression scales at baseline and at 40, 80, 120, and 230 minutes postinfusion. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale score. BDNF levels were obtained at the same time points as depression rating scale scores.ResultsDespite a significant (P <. 001) improvement in MADRS scores after subjects received ketamine treatment, no changes in BDNF levels were observed in subjects after they received ketamine compared to baseline. Also, no association was found between antidepressant response and BDNF levels.ConclusionsThis study demonstrates that ketamine's rapid initial antidepressant effects are not mediated by BDNF. Further studies are necessary to shed light on the neurobiological basis of these effects.Trial registrationclinicaltrials.gov Identifiers: NCT00024635 and NCT00088699.
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Project description:BackgroundEvidence demonstrates that brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100B) have a pivotal role in the pathogenesis of major depressive disorder (MDD) and they are proposed as predictors of antidepressant response. Ketamine produces rapid antidepressant effects in MDD and pre-clinical studies suggest the necessity of increased BDNF levels for the antidepressant action of ketamine. However, studies observing the change of blood BDNF levels after ketamine intervention are inconsistent and studies about the role of plasma S100B in ketamine administration in MDD patients are lacking.MethodWe evaluated mature BDNF (mBDNF), S100B levels in plasma and their associations with depression severity in 30 Selective Serotonin Reuptake Inhibitor (SSRI)-resistant MDD patients enrolled in a randomized controlled trial of ketamine compared (n = 20) to a placebo (n = 10) control (saline). Severity of depression was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS).ResultsPlasma mBDNF and S100B were not significantly changed after 1-2 days of single ketamine compared to placebo. Plasma mBDNF and S100B levels did not significantly differ in responders compared to non-responders of ketamine treatment. The change of plasma mBDNF levels was positively correlated with the improvement of MADRS score after 1-2 weeks of open-label ketamine treatment (rho = 0.495, p = 0.031), though this change did not survive correction for multiple comparisons.ConclusionThese findings do not support the hypothesis that ketamine treatment increases BDNF plasma levels in MDD patients. No effect of ketamine treatment on S100B plasma levels was seen.
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Project description:The brain-derived neurotrophic factor (BDNF) is a secretory growth factor that promotes neuronal proliferation and survival, synaptic plasticity and long-term potentiation in the central nervous system. Brain-derived neurotrophic factor biosynthesis and secretion are chrono-topically regulated processes at the cellular level, accounting for specific localizations and functions. Given its role in regulating brain development and activity, BDNF represents a potentially relevant gene for schizophrenia, and indeed BDNF and its non-synonymous functional variant, rs6265 (C ? T, Val ? Met) have been widely studied in psychiatric genetics. Human and animal studies have indicated that brain-derived neurotrophic factor is relevant for schizophrenia-related phenotypes, and that: (1) fine-tuned regulation of brain-derived neurotrophic factor secretion and activity is necessary to guarantee brain optimal development and functioning; (2) the Val ? Met substitution is associated with impaired activity-dependent secretion of brain-derived neurotrophic factor; (3) disruption of brain-derived neurotrophic factor signaling is associated with altered synaptic plasticity and neurodevelopment. However, genome-wide association studies failed to associate the BDNF locus with schizophrenia, even though a sub-threshold association exists. Here, we will review studies focused on the relationship between the genetic variation of BDNF and schizophrenia, trying to fill the gap between genetic risk per se and insights from molecular biology. A deeper understanding of brain-derived neurotrophic factor biology and of the epigenetic regulation of brain-derived neurotrophic factor and its interactome during development may help clarifying the potential role of this gene in schizophrenia, thus informing development of brain-derived neurotrophic factor-based strategies of prevention and treatment of this disorder.
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