Elsevier

Biological Psychiatry

Volume 50, Issue 4, 15 August 2001, Pages 260-265
Biological Psychiatry

Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication

https://doi.org/10.1016/S0006-3223(01)01083-6Get rights and content

Abstract

Background: The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain

Methods: Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry

Results: Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death

Conclusions: These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.

Introduction

Cell signaling abnormalities may be critical to the pathophysiology and treatment of major depressive disorder (MDD) (Duman et al 1997). Postmortem brain studies report changes at multiple sites of the cAMP pathway in MDD Cowburn et al 1994, Dowlatshahi et al 1999, Dowlatshahi et al 1998, Lowther et al 1997, Reiach et al 1999. Antidepressant (AD) treatment and electroconvulsive shock (ECS) consistently upregulate several components of this pathway in rat and mouse brain, including CREB and phosphorylated CREB levels, and these effects may be important in their mechanism of action Fitzgerald et al 1996, Jensen et al 2000, Jeon et al 1997, Mori et al 1998, Nibuya et al 1996, Pilc and Legutko 1995a, Pilc and Legutko 1995b, Shimizu et al 1995, Takahashi et al 1999, Thome et al 2000. Studies of downstream targets of the cAMP pathway revealed that brain derived neurotrophic factor (BDNF), which regulates neuronal survival and synaptic plasticity, is also increased by AD and ECS in cerebral cortex and hippocampus Fujimaki et al 2000, Nibuya et al 1995

We previously reported a decrease in the transcription factor CREB in cerebral cortex of subjects with MDD, that is restored in MDD subjects treated with AD at the time of death (Dowlatshahi et al 1998). Using the same tissue sample, another laboratory found increased levels of the mRNA for the BDNF receptor, trkB, associated with AD treatment (Bayer et al 2000). With the recent availability of hippocampal sections from subjects with MDD, bipolar disorder (BD) and schizophrenia (SCZ), we were able to measure BDNF using immunohistochemistry, as this may be a critical target in MDD and its treatment with antidepressant medications

Section snippets

Postmortem brain samples

Frozen postmortem anterior hippocampal sections were obtained from the Stanley Foundation Neuropathology Consortium consisting of subjects with MDD, BD, SCZ and age and gender matched control subjects (n = 15 per group). Diagnoses were retrospectively established by two senior psychiatrists using DSM-IV criteria. Detailed clinical information and diagnostic procedures are provided elsewhere (Dowlatshahi et al 1999). As previously described, of the sections obtained from the 60 subjects, we were

Results

The specificity of the BDNF antisera was confirmed with SH-SY5Y cell extract and recombinant BDNF (Figure 1A). As expected, this antisera detected a 14 Kd band in cellular extract (Murer et al 1999). In frozen postmortem sections, we were able to detect BDNF immunoreactivity in several regions of anterior hippocampus. High levels of immunoreactivity were detected in hilus, dentate gyrus as well as supragranular regions adjacent to the dentate gyrus. Lower levels were detected in other regions,

Discussion

These results add further support to the notion that BDNF may be regulated by AD medications, suggesting its possible involvement in the pathophysiology of MDD, and possibly depressive symptoms in BD and schizophrenia. These results provide the first demonstration from patient samples that BDNF may be regulated by AD medications that target the cAMP signaling system, and lend further support to previous animal studies in which similar effects have been consistently shown. Increased hippocampal

Acknowledgements

This work was supported by the Medical Research Council of Canada (LTY, GMM, JFW), the Theodore and Vada Stanley Foundation (LTY), and the National Science and Engineering Research Council of Canada (DD). BC is a Fellow of the Canadian Psychiatric Research Foundation. LTY is a Career Scientist of the Ontario Ministry of Health. GMM is a CIHR New Investigator. Postmortem brains were donated by the Stanley Foundation Brain Consortium courtesy of Drs. Llewellyn B. Bigelow, Juraj Cervenak, Mary M.

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