Adenylyl cyclase-cyclicAMP signaling in mood disorders: Role of the crucial phosphorylating enzyme protein kinase A

Mood disorders are among the most prevalent and recurrent forms of psychiatric illnesses. In the last decade, there has been increased understanding of the biological basis of mood disorders. In fact, novel mechanistic concepts of the neurobiology of unipolar and bipolar disorders are evolving based on recent pre-clinical and clinical studies, most of which now focus on the role of signal transduction mechanisms in these psychiatric illnesses. Particular investigative emphasis has been given to the role of phosphorylating enzymes, which are crucial in regulating gene expression and neuronal and synaptic plasticity. Among the most important phosphorylating enzyme is protein kinase A (PKA), a component of adenylyl cyclase–cyclic adenosine monophosphate (AC–cAMP) signaling system. In this review, we critically and comprehensively discuss the role of various components of AC–cAMP signaling in mood disorders, with a special focus on PKA, because of the interesting observation that have been made about its involvement in unipolar and bipolar disorders. We also discuss the functional significance of the findings regarding PKA by discussing the role of important PKA substrates, namely, Rap-1, cyclicAMP-response element binding protein, and brain-derived neurotrophic factor. These studies suggest the interesting possibility that PKA and related signaling molecules may serve as important neurobiological factors in mood disorders and may be relevant in target-specific therapeutic interventions for these disorders

Region-specific alterations in the corticotropin-releasing factor and glucocorticoid receptors in the postmortem brain of suicide victims

Rationale : Abnormalities of hypothalamic–pituitary–adrenal (HPA) axis in depression and suicide are among the most consistent findings in biological psychiatry. However, the specific molecular mechanism associated with HPA axis abnormality in the brain of depressed or suicidal subjects is not clear. It is believed that abnormal HPA axis is caused by increased levels of corticotropin-releasing factor (CRF) and decreased levels of glucocorticoid receptor (GR) in the brain of depressed or suicide subjects. To study their role in teenage suicide, we determined the protein and gene expression of CRF, CRF receptors, and GR in the prefrontal cortex (PFC), hippocampus, and amygdala of teenage suicide victims and teenage normal control subjects. Methods : The postmortem brain samples were obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center, Baltimore, MD, USA. Samples were obtained from 24 teenage suicide victims and 24 normal teenage control subjects. Psychological autopsy was performed and the subjects were diagnosed according to the DSM-IV (SCID). Protein expression was determined using Western blot and gene expression (mRNA) was determined using real-time RT-polymerase chain reaction (qPCR) technique. Results : We observed that the protein and gene expression of the CRF was significantly increased in the PFC (Brodmann area 9) and in amygdala, but not in the hippocampus, of teenage suicide victims compared with normal control subjects. The protein and gene expression of CRF-R1 was significantly decreased in the PFC and amygdala, but not in the hippocampus, of suicide victims. We also observed a significant decrease in the protein and mRNA expression of GR in the PFC and amygdala, but not in the hippocampus, of teenage suicide victims compared with control subjects. Conclusion : These results thus indicate that suicidal behavior is associated with increased CRF and decreased GR in certain specific areas of the brain of suicide victims compared with controls

β-Adrenergic receptor subtypes in stress-induced behavioral depression

The purpose of this study was to examine the role of β-adrenergic receptors in an animal model of stress-induced behavioral depression. β-Adrenergic receptors in several brain regions and leukocytes of rats were determined by receptor binding techniques using 125I-cyanopindolol (cyp) as ligand and propranolol as displacer for total β-adrenergic receptors, and ICI 86,406 for β 1- and ICI 118, 551 for β 2-adrenergic receptors. We observed that the maximum number of binding sites ( B max) and the apparent dissociation constant ( K d ) of 125I-cyp binding to total β-adrenergic receptors were increased in hippocampus of stressed rats with escape deficits (48 h after training) as compared to control rats. This increase was due to an increase in B max and K d of 125I-cyp binding to β 1-adrenergic receptors but not to β 2-adrenergic receptors. There was no significant difference in β 1-adrenergic receptors in cortex and cerebellum or β 2-adrenergic receptors in hippocampus, cortex, cerebellum, or leukocytes of stressed (48 h after training) rats with escape deficits as compared to control rats. Interestingly, it was observed that β 1- and β 1-adrenergic receptors in various brain regions (cortex, cerebellum, and hippocampus) and β 2-adrenergic receptors in leukocytes of stressed rats (10 days after training) were not significantly different from control rats, although escape deficits were still present. These results suggest that abnormalities in adrenergic neurotransmission are associated with an upregulation of β 1-adrenergic receptors, which in turn may be involved in the early stages of behavioral deficits caused by uncontrollable shock

Expression of p21-activated kinases 1 and 3 is altered in the brain of subjects with depression

The p21-activated kinases (PAKs) of group I are the main effectors for the small Rho GTPases, critically involved in neurodevelopment, plasticity and maturation of the nervous system. Moreover, the neuronal complexity controlled by PAK1/PAK3 signaling determines the postnatal brain size and synaptic properties. Stress induces alterations at the level of structural and functional synaptic plasticity accompanied by reductions in size and activity of the hippocampus and the prefrontal cortex (PFC). These abnormalities are likely to contribute to the pathology of depression and, in part, reflect impaired cytoskeleton remodeling pointing to the role of Rho GTPase signaling. Thus, the present study assessed the expression of the group I PAKs and their activators in the brain of depressed subjects. Using quantitative polymerase chain reaction (qPCR), mRNA levels and coexpression of the group I PAKs: PAK1, PAK2, and PAK3 as well as of their activators: RAC1, CDC42 and ARHGEF7 were examined in postmortem samples from the PFC (n = 25) and the hippocampus (n = 23) of subjects with depression and compared to control subjects (PFC n = 24; hippocampus n = 21). Results demonstrated that mRNA levels of PAK1 and PAK3, are significantly reduced in the brain of depressed subjects, with PAK1 being reduced in the PFC and PAK3 in the hippocampus. No differences were observed for the ubiquitously expressed PAK2. Following analysis of gene coexpression demonstrated disruption of coordinated gene expression in the brain of subjects with depression. Abnormalities in mRNA expression of PAK1 and PAK3 as well as their altered coexpression patterns were detected in the brain of subjects with depression.Fil: Fuchsova, Beata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Alvarez Juliá, Anabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Rizavi, Hooriyah S.. University of Illinois; Estados UnidosFil: Frasch, Alberto Carlos C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas ; ArgentinaFil: Pandey, Ghanshyam N.. University of Illinois; Estados Unido