Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication
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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