The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair

OPEN Citation: Transl Psychiatry (2017) 7, e1233; doi:10.1038/tp.2017.205 www.nature.com/tp ORIGINAL ARTICLE The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair M Notaras1,2,3, X Du2,4, J Gogos5, M van den Buuse1,6,7,8 and RA Hill1,2,4 The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression. Translational Psychiatry (2017) 7, e1233; doi:10.1038/tp.2017.205; published online 19 September 2017 INTRODUCTION Affective disorders, such as major depressive disorder, have an estimated lifetime prevalence of ~ 20.8%,1 and are projected to become a leading cause of long-term disability.2 The neurobiology of affective disorders has advanced rapidly, and has led to the identification of a number of core pathology that includes reduced neurotrophic support and synaptic remodeling3 within brain regions such as the hippocampus4,5 and medial prefrontal cortex (mPFC).5 One environmental factor that has consistently been associated with the onset and maintenance of affective disorders is stress. Clinical markers of stress exposure, such as daily life stress, history of stressful life events, and trauma have all been shown to play a role in aspects of affective disorder symptomology or risk, and collectively support the assertion that both developmental and ongoing stress are capable of inducing depressive disorders.6 In rodent models, exposure to a broad range of stress paradigms has led to the identification of several remodeling events that putatively occur as a result of glucocorticoid stress hormones within the brain. These include widespread alterations within the hippocampus, including reductions in dendritic spine branching and complexity,7 changes in the expression of brain-derived neurotrophic factor (BDNF),8 NMDA receptor subunit reorganization9 and synaptic scaffolding proteins such as the excitatory postsynaptic molecule PSD-9510 and presynaptic marker synaptophysin.11 A similar pattern of reorganization following stress also occurs in other brain regions including the mPFC, which appears particularly vulnerable to stress-induced alterations in noradrenergic activity12,13 and the maturation of inhibitory interneuron networks.14 BDNF has been widely studied as a susceptibility factor for both stress and affective dysregulation. BDNF plays a fundamental role in brain development, neuronal differentiation and synaptic plasticity.15 It has been suggested that BDNF is a transducer of antidepressant effects,16 principally because BDNF is recruited by antidepressant therapeutics (as well as other mood disorder treatments such as electroconvulsive shock17 and transcranial magnetic stimulation therapies18) and is suppressed by many risk factors for mood disorders including stress.19 In rodent models, BDNF also mediates behavioral endophenotypes of relevance to affective disorders,20,21 while in clinical samples serum BDNF concentrations predict the effectiveness of selective-serotonin reuptake inhibitors in the treatment of depression.22 The BDNF Val66Met polymorphism, named after a Valine → Methionine substitution at codon 66 within the BDNF prodomain, has been widely studied as a risk factor for affective disorders due to its common frequency and established functionality.15 Specifically, the Val66Met substitution results in the diminished activity- 1 Behavioural Neuroscience Laboratory, Florey Institute of Neuroscience & Mental Health, Parkville, VIC, Australia; 2Psychoneuroendocrinology Laboratory, Florey Institute of Neuroscience & Mental Health, Parkville, VIC, Australia; 3Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA; 4Department of Psychiatry, Monash University, Melbourne, VIC, Australia; 5Departments of Biophysics & Neuroscience, Columbia University, New York, NY, USA; 6School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia; 7Department of Pharmacology, University of Melbourne, Melbourne, VIC, Australia and 8College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia. Correspondence: Professor M van den Buuse or RA Hill, School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia. E-mail: Received 24 March 2017; revised 21 June 2017; accepted 5 July 2017 BDNF val66met glucocorticoid interaction M Notaras et al 2 dependent release of BDNF,23 deficient hippocampus-dependent memory function24 and a lack of response to antidepressant therapeutics in BDNFVal66Met knock-in mice.24,25 However, the role of this gene variant as a risk factor for mood disorders and modulator of antidepressant response has been the source of much controversy given non-concordant results between association studies (see ref. 15 for extensive review). These inconsistent clinical findings strengthen the case for animal models in providing well controlled findings on the biological mechanisms which underpin stress responsivity, as well as antidepressant response. That said, a number of reports have emerged in recent years which suggest that the Val66Met variant may induce HPA axis dysfunction,25 which we previously hypothesized may lead to a long-lasting sensitivity to glucocorticoid stress hormones15 and thus vulnerability to affective dysregulation. In support of this hypothesis, it has been previously published that childhood adversity may unmask an effect of the 66Met allele on depression,26 while in otherwise healthy adults a history of sexual trauma has been (...truncated)