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, 37 (3), 596-603

Altered Expression of Apoptotic Factors and Synaptic Markers in Postmortem Brain From Bipolar Disorder Patients

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Altered Expression of Apoptotic Factors and Synaptic Markers in Postmortem Brain From Bipolar Disorder Patients

Hyung-Wook Kim et al. Neurobiol Dis.

Abstract

Bipolar disorder (BD) is a progressive psychiatric disorder characterized by recurrent changes of mood and is associated with cognitive decline. There is evidence of excitotoxicity, neuroinflammation, upregulated arachidonic acid (AA) cascade signaling and brain atrophy in BD patients. These observations suggest that BD pathology may be associated with apoptosis as well as with disturbed synaptic function. To test this hypothesis, we measured mRNA and protein levels of the pro-apoptotic (Bax, BAD, caspase-9 and caspase-3) and anti-apoptotic factors (BDNF and Bcl-2) and of pre- and post-synaptic markers (synaptophysin and drebrin), in postmortem prefrontal cortex (Brodmann area 9) from 10 BD patients and 10 age-matched controls. Consistent with the hypothesis, BD brains showed significant increases in protein and mRNA levels of the pro-apoptotic factors and significant decreases of levels of the anti-apoptotic factors and the synaptic markers, synaptophysin and drebrin. These differences may contribute to brain atrophy and progressive cognitive changes in BD.

Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mean BAD protein (a) (with representative immunoblot) in control (n = 10) and BD frontal cortex (n = 10). Data are ratios of optical densities of BAD protein to β-actin, expressed as percent of control. mRNA level of bad (b) in postmortem control (n = 10) and BD (n = 10) frontal cortex, measured using real time RT-PCR. Data are mRNA level of bad in the BD patients normalized to the endogenous control (β-globulin) and relative to control level (calibrator), using the ΔΔCT method. Mean ± SEM, *p < 0.05, **p < 0.01.
Figure 2
Figure 2
Representative immunoblot of Bcl-2 (a) and Bax protein level (c) in frontal cortex of controls (n = 10) and BD patients (n = 10). Data are ratios of optical density of Bcl-2 and Bax to β-actin, expressed as percent of control. mRNA level of bcl-2 (b) and bax (d) in postmortem control (n = 10) and BD (n = 10) frontal cortex, measured using real time RT-PCR. Bar graph (e) is Bax to Bcl-2 ratio in frontal cortex of controls and BD patients. Mean ± SEM, *p < 0.05, **p < 0.01.
Figure 3
Figure 3
Representative immunoblot of Caspase-9 (a) and -3 (c) protein levels in frontal cortex of controls (n = 10) and BD patients (n = 10). Data are ratios of optical density of Caspases to β-actin, expressed as percent of control. mRNA levels of Caspase-9 (b) and -3 (d) in postmortem control (n = 10) and BD (n = 10) frontal cortex, measured using real time RT-PCR. Mean ± SEM, *p < 0.05, ***p < 0.001. (e) Representative histology of control and BD frontal cortex. Active Caspase-3 was detected by kit as described in materials and methods. Scale bar, 100 μm (lower) and 20 μm (upper). Red stains indicated by arrows represent the expression of active Caspase-3 in BD frontal cortex. Counterstaining was performed using methyl green.
Figure 4
Figure 4
Protein level of BDNF (a) was determined by ELISA. mRNA levels of BDNF (b) in postmortem control (n = 10) and BD (n = 10) frontal cortex, measured using real time RT-PCR. Mean ± SEM, **p < 0.01, *** < 0.001.
Figure 5
Figure 5
Representative immunoblot of Synaptophysin (a) and Drebrin (c) protein levels in frontal cortex of controls (n = 10) and BD patients (n = 10). Data are ratios of optical density of synaptophysin and drebrin to β-actin, expressed as percent of control. mRNA levels of Synaptophysin (b) and Drebrin (d) in postmortem control (n = 10) and BD (n = 10) frontal cortex, measured using real time RT-PCR. Mean ± SEM, *p < 0.05, **p < 0.01, *** < 0.001.
Figure 6
Figure 6
Schematic diagram of apoptotic pathway in brain of bipolar disorder patients. Various stimuli can initiate apoptosis cascade, including diseases. Once triggered, pro-apoptotic factor BAD is dissociated from the complex with 14-3-3ζ, and replace anti-apoptotic factor Bcl-2, leading to release cytochrome C from mitochondria, which in turn activates Capases-9 and Caspase-3. Apoptotic change may result in loss of synaptic integrity with decreased expression of synaptic markers, Synaptophysin and Drebrin.

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