Protein kinase C in the postmortem brain of teenage suicide victims

doi:10.1016/S0304-3940(97)00378-9

Neuroscience Letters

Volume 228, Issue 2, 6 June 1997, Pages 111-114

https://doi.org/10.1016/S0304-3940(97)00378-9 Get rights and content

Abstract

Increased serotonin_2A (5-HT_2A) receptors have been reported in the postmortem brain of suicide victims. To examine if this increase is associated with the dysregulation of postreceptor sites in the signaling cascade, we determined [³H]phorbol dibutyrate (PDBU) binding to protein kinase C (PKC) in postmortem brain samples (Brodmann's areas 8 and 9) obtained from teenage suicide victims and control subjects. [³H]PDBU binding to PKC was determined in membranal and cytosolic fractions. We observed that B_max of [³H]PDBU binding sites was significantly decreased in both membranal and cytosolic fractions in brain samples from Brodmann's areas 8–9 compared to matched controls. These results thus suggest that PKC may play a role in the pathophysiology of suicidal behavior.

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Acknowledgements

This work was supported by a grant from the National Institute of Mental Health (ROIMH 48153-04 and MH 40279). We acknowledge with thanks the cooperation of Dr. John Smailek, Chief Medical Examiner, and Dr. Dennis Chute, Assistant Medical Examiner, in the collection of brain samples, and Ms. Terri U'Prichard for performing the psychological autopsies.

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Abnormalities of protein kinase C (PKC) have been implicated in the pathophysiology of bipolar (BP) illness. This is primarily based on studies of PKC in platelets of BP patients. Whether such abnormalities of PKC activity and isoforms exist in the brain is unclear. We have therefore determined PKC activity, protein and mRNA expression of PKC isoforms in the prefrontal cortex (PFC), cingulate cortex (CING) and temporal cortex (TEMP) from BP (n = 19), schizophrenic (SZ) (n = 20) and normal control (NC) (n = 25) subjects. The brain samples were obtained from the Harvard Brain Bank, and the subjects were diagnosed according to DSM-IV criteria. Protein levels were determined using Western blot technique and mRNA levels were determined using real-time PCR (qPCR) method. We found that there was a significant decrease in the PKC activity in the cytosol and membrane fractions of PFC and TEMP obtained from BP subjects but not from SZ subjects. When we compared the expression of PKC isozymes, we found that the protein and mRNA expression of several isozymes was significantly decreased in the PFC (i.e., PKCα, PKCβI, PKCβII and PKCε) and TEMP (i.e., PKCα, PKCβI, PKCβII, PKCε and PKCγ) of BP subjects, but not in the CING. Overall, there was no difference in the mRNA or protein expression of PKC isozymes between SZ and NC subjects in any of the three brain areas we studied. Our results show that there is a region-specific decrease of certain PKC isozymes in the membrane and cytosol fractions of BP but not SZ subjects.
Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2
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Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid.
Mice were treated orally with ursolic acid (0.1 mg/kg) and, 45 min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1 μg/mouse), KN-62 (CAMK-II inhibitor, 1 μg/mouse), chelerythrine (PKC inhibitor, 1 μg/mouse), U0126 (MEK1/2 inhibitor, 5 μg/mouse), PD98059 (MEK1/2 inhibitor, 5 μg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1 μg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST).
The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002.
These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid.
Neurobiology of chronic mild stress: Parallels to major depression
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Citation Excerpt :
Similarly, protein levels of AC (Cowburn et al., 1994; Reiach et al., 1999) as well as stimulated levels of AC activity (Cowburn et al., 1994; Lowther et al., 1996; Dowlatshahi et al., 1999; Valdizan et al., 2003) were reduced in the frontal and temporal cortex of depressed subjects. PKC activity, conversely, has been either reduced (Pandey et al., 1997, 2003) or unchanged (Hrdina et al., 1998) in the frontal cortex and hippocampus of suicide victims, similar to the contrasting reports seen following CMS. Collectively, these human data would suggest that the AC-cAMP-PKA signaling cascade is reduced in depression, particularly in the frontal cortex, which corresponds very well with the reductions in this signaling pathway following CMS.
The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.
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Platelet protein kinase C and brain-derived neurotrophic factor levels in borderline personality disorder patients
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Citation Excerpt :
From a pharmacologic perspective, preclinical studies have shown that chronic administration of antidepressants (fluoxetine and desipramine) decreases PKC activity in the cortex and hippocampus of rats (Mann et al., 1995). In teenaged suicide victims PKC in prefrontal (Brodmann Area 8 (BA8) and BA9) brain tissue is reduced in membranal and cytosolic fractions compared with age-matched controls who died of causes other than suicide (Pandey et al., 1997). In a subsequent study of prefrontal and hippocampal postmortem tissue from teenage suicide victims, Pandey et al. found decreased membrane and cytosolic fraction PKC activity, decreased levels in both fractions of the isoenzymes PKC-α, PKC-βI, PKC-βII, PKC-γ, and of their respective m-RNA's (Pandey et al., 2004).
Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-α, phosphorylated-PKC-α (p-PKCα), PKC-βII, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-α levels were lower in patients than controls. p-PKC-α and PKC-βII were lower at trend levels. In the entire sample, platelet p-PKCα and PKC-α activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide.
The role of microRNAs in synaptic plasticity, major affective disorders and suicidal behavior
2012, Neuroscience Research
Major affective disorders are common widespread conditions associated with multiple psychosocial impairments and suicidal risk in the general population. At least 3–4% of all depressive individuals die by suicide. At a molecular level, affective disorders and suicidal behavior are recently associated with disturbances in structural and synaptic plasticity. A recent hypothesis suggested that small non-coding RNAs (ncRNAs), in particular microRNAs (miRNAs), play a critical role in the translational regulation at the synapse. We performed a selective overview of the current literature on miRNAs putative subcellular localization and sites of action in mature neurons analyzing their role in neurogenesis, synaptic plasticity, pathological stress changes, major affective disorders and suicidal behavior. miRNAs have played a fundamental role in the evolution of brain functions. The perturbation of some intracellular mechanisms as well as impaired assembly, localization, and translational regulation of specific RNA binding proteins may affect learning and memory, presumably contributing to the pathogenesis of major affective disorders and perhaps suicidal behavior. Also, miRNA dys-regulation has also been linked to several neuropsychiatric diseases. However, further evidence are needed in order to directly clarify the role of miRNAs in major affective disorders and suicidal behavior.

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Protein kinase C in the postmortem brain of teenage suicide victims

Abstract

Section snippets

Acknowledgements

Life Sci.

Life Sci.

Biol. Psychiatry

J. Affect. Dis.

Biol. Psychiatry

J. Biol. Chem.

J. Pharmacol. Methods

J. Biol. Chem.

Biol. Psychiatry

Psychiat. Res.

Lancet

Lancet

Calcium-mobilizing receptors, polyphosphoinositides, and the generation of second messengers

Pharmacol. Rev.

Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid

Psychiat. Res.

Serotonergic measures in the brain of suicide victims: 5HT2 binding sites in the frontal cortex of suicide victims and control subjects

Am. J. Psychiatry

Serotonergic measures in the brain of suicide victims: 5HT₂ binding sites in the frontal cortex of suicide victims and control subjects