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

Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago Chicago, Illinois 60612, USA.
Neuropsychiatric Disease and Treatment (Impact Factor: 2.15). 03/2008; 4(1):161-76. DOI: 10.2147/NDT.S2380
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mood disorders have powerful effects on the lives of many people. Finding the mechanisms underlying these disorders is essential to develop selective treatment. In this thesis, interspecies trait genetics are used on behavioural domains to unravel the complex genetics of involved endophenotypes. We developed a home cage environment, allowing automated multi-day recordings, assessing the animals’ reduced preference for exposed areas (avoidance behaviour) independent of motor activity levels. To efficiently screen for genetic loci of interest, we used chromosome substitution strains (CSS) of mice; inbred strains with an A/J chromosome substituting the corresponding chromosome in the C57BL/6J background. Following behavioral testing of the full panel of chromosome substitution strains in the home cage environment, we were able to select particular strains of interest and, by the use of a F2-population, map different genetic loci specific for motor activity levels and avoidance behaviour. We genetically mapped the expression of baseline motor activity levels to mouse chromosome 1. By data mining an existing phenotypic and genotypic data set of genetically heterogeneous mice, we refined the QTL to a 312 kb interval containing a single gene (A830043J08Rik). Genome-wide microarray gene expression profiling showed a significant up-regulation of Epha4 in low active F2-individuals. Neuro-anatomical research in the spinal cord and ventral roots revealed considerable differences in motor neuron morphology, with A/J and CSS1 having smaller, possibly less developed, motor neuron axons. Also, for CSS1 and C57BL/6J, a correlation was found between motor activity levels, uncoordinated hind limb movement and neuro-anatomical differences in the cortico-spinal tract. This thesis also shows that both chromosome 15 and 19 are involved in avoidance behaviour. For chromosome 15, a small genetic region was found associated with this behavior. This QTL proved to be homologous with a human linkage region for bipolar disorder. By combining mouse SNP data with the WTCCC GWA study, 2 genes of interest were identified, showing allele frequency differences between healthy controls and bipolar patients. Only Adcy8 was differentially expressed as a function of mouse avoidance behavior in brain regions associated with mood regulation. Since Adcy8 mutant mice show altered anxiety-related behavior and the functioning of the adenylyl cyclase (AC) system is known to be changed in bipolar patients and is a target for mood stabilizers, we conclude that this gene encodes a behavioral endophenotype of bipolar disorder. Activation of AC causes the conversion of ATP to cAMP, activating (amongst others) protein kinase A (PKA). Interestingly, the QTL on mouse chromosome 19 was also found to be homologous with a human bipolar linkage region and contains genes which are functional in the PKA signaling pathway. If the changes in behavior observed in CSS15 and CSS19 are indeed caused by changes in the AC-cAMP signaling pathway, testing these and other strains in the home cage environment as described in this thesis can provide great opportunities not only to screen for other genes and cascades related to this pathway, but also to use a genetically validated model to search for effective treatment options influencing this biological signaling pathway.
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.
    PLoS ONE 12/2013; 8(12):e82262. DOI:10.1371/journal.pone.0082262 · 3.53 Impact Factor

Preview (2 Sources)

1 Download
Available from