Neuroscience Letters 600 (2015) 12–16
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Gender and brain regions speciﬁc differences in brain derived neurotrophic factor protein levels of depressed individuals who died through suicide Shawn Hayley a,∗ , Lisheng Du b , Darcy Litteljohn a , Miklós Palkovits c , Gábor Faludi d , Zul Merali b , Michael O. Poulter e , Hymie Anisman a a
Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada c Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary d Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary e Robarts Research Institute, University of Western Ontario, London, Ontario, Canada b
h i g h l i g h t s • • • •
We utilized a modiﬁed Western blot procedure to assess central BDNF levels in depressed suicides and matched control subjects. Protein levels of BDNF differed between suicide and control subjects. BDNF levels also varied as a function of gender. The hippocampus and frontal cortex displayed decreased patterns of BDNF depending on gender.
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Article history: Received 20 March 2015 Received in revised form 21 May 2015 Accepted 24 May 2015 Available online 29 May 2015 Keywords: BDNF Suicide Depression Gender Postmortem Neuroplasticity
a b s t r a c t Considerable evidence supports the view that depressive illness and suicidal behaviour stem from perturbations of neuroplasticity. Presently, we assessed whether depressed individuals who died by suicide displayed brain region-speciﬁc changes in brain derived neurotrophic factor (BDNF) and whether such effects varied by gender. Using postmortem samples from non-psychiatric controls and depressed individuals who died by suicide, BDNF protein levels were assessed within the hippocampus and frontopolar prefrontal cortex using Western blot. As expected, BDNF levels were reduced within the frontopolar prefrontal cortex among female depressed suicides; however, males showed no such effect. Contrastingly, within the hippocampus, depressed male but not female suicides displayed signiﬁcant reductions of BDNF protein levels. Although the mechanisms driving the gender and brain region speciﬁc BDNF changes are unclear, our data do support the notion that complex alterations of neuroplasticity may be fundamentally involved in the illness. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Depressive disorders commonly have a high degree of relapse and may be life-long in many cases . Major depression has been associated with both structural and functional changes within limbic regions, such as the hippocampus and amygdala [2,3], and the
Abbreviations: BDNF, Brain derived neurotropic factor; SSRI, Selective serotonin reuptake inhibitor; PFC, Prefrontal cortex. ∗ Corresponding author at. Department of Neuroscience, Carleton University, 1125Colonel By Drive, Ottawa, ON, K1S5B6. Tel.: +1 6135202600x6314. E-mail address: shawn [email protected]
(S. Hayley). http://dx.doi.org/10.1016/j.neulet.2015.05.052 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.
extent of hippocampal volume reduction was related to illness duration [2,4]. Additionally, decreased dendritic branching within anterior cingulate neurons , along with a loss of frontal cortex synapses was observed in depressed subjects [6,7]. Thus, depression might involve deﬁcits in neural “circuits” that underlie the processing of emotional stimuli [8,9]. Animal models of depression have revealed that stressors induce deﬁcits in neuroplasticity, with these changes being related to reduced expression of brain derived neurotrophic factor (BDNF) [10–12]. These BDNF deﬁcits have been linked to impairments of dendritic branching and neurogenesis, which can favor pathological outcomes [11,13]. In fact, BDNF knockdown
S. Hayley et al. / Neuroscience Letters 600 (2015) 12–16
within the hippocampus reduced neurogenesis and precipitated depressive-like behaviours, and conversely, hippocampal BDNF over-expression promoted resilience to chronic stressor exposure [14,15]. Similarly, central infusion of BDNF itself induced an antidepressant-like effect , and virtually all existing antidepressant treatments increased hippocampal neurogenesis and BDNF expression [9,17–19]. Limited information is available concerning brain BDNF protein levels among depressed individuals who died by suicide. A few reports suggested a link between compromised BDNF signaling within the hippocampus, amygdala and/or cortex, as well as in peripheral immune cells and suicide among depressed individuals [20–22]. Reductions of BDNF in the hippocampus and prefrontal cortex were also reported in mixed psychiatric populations that died by suicide [23–25]. Thus, BDNF may act as a general “vulnerability” factor for psychiatric illness, rather than one that speciﬁcally linked to depressive disorders. That said, it is critical to determine the pattern of brain region-speciﬁc BDNF changes that might underlie suicidal behavior in depressive illness and whether a sexual dimorphism exists. This is particularly important given that depression is more common in women, but suicide more frequent in men . Hence, we assessed gender-dependent changes in BDNF protein levels within the hippocampus and frontopolar prefrontal cortex (FPC) among depressed individuals who died by suicide, relative to those that died suddenly through other causes.
Examination of the medical records of controls indicated the absence of a history of psychiatric illness, alcohol or drug abuse during the preceding ten years. This was conﬁrmed through interviews with family members. As shown in Table 1, the cause of death in control subjects was acute cardiac failure (ACF), myocardial infarction (AMI) or in one case, a trafﬁc accident. Thus, the cause of death was unrelated to psychiatric illness or suicide. 2.2. Tissue collection and dissection Brains were dissected, rapidly frozen on dry ice and stored at −80 ◦ C until microdissection (2 days -2 months later). Brain samples were sliced into 1–1.5 mm thick coronal sections at a temperature between 0 and −10 ◦ C. The frontopolar prefrontal cortex (FPC - Brodmann area 10 and small portion of Brodman area 9) was dissected by a Graefe’s microdissecting knife at the most polar portion of the right frontal lobe, below the intermediate frontal sulcus. Samples from the hippocampus were taken bilaterally from two consecutive coronal sections of the frontal portion of the temporal lobe. Two tissue pellets were punched from each hippocampal section with a 1.5 mm needle on each side. The tissue pellets included the dentate gyrus, all of the hippocampal areas (CA1–CA3), and a portion of the subiculum; neither the presubiculum nor the parahippocampal gyrus was included. The samples were stored in airtight containers or plastic tubes at −80 ◦ C until further use. 2.3. Western blot analysis
2. Methods 2.1. Participants Brains from suicides and control participants who died suddenly from causes not directly involving any diseases of the central nervous system (Age = 51.3 ± 4.00 and 45.0 ± 3.40, respectively), were obtained at autopsy at the Department of Forensic Medicine of the Semmelweis University Medical School. All controls and individuals who died by suicide were Caucasian from Hungary (Budapest region). Table 1 provides a description of cause of death for individuals in each condition, the postmortem interval for brain sectioning to begin (PMI), and the RNA integrity numbers (RIN) and pH for tissue samples. Tissue harvesting occurred after written informed consent was obtained from next of kin. The local ethics committee at Semmelweis and the Ethics Committees of Carleton University and the University of Western Ontario approved the harvesting and analysis of the tissue samples. Brain samples were obtained very soon after death (