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Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain

Adam J Funk1, Robert E McCullumsmith, Vahram Haroutunian

  • 1Department of Neurobiology, University of Alabama Birmingham, Birmingham, AL 35294-0021, USA. adamfunk@uab.edu

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|November 4, 2011
PubMed

Insights

Schizophrenia may involve altered intracellular signaling pathways in the brain. This study found specific protein changes in the anterior cingulate and dorsolateral prefrontal cortex, suggesting abnormal mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) pathway activity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Psychiatry

Background:

  • Schizophrenia pathophysiology may involve dysregulation of intracellular signaling pathways.
  • Mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) pathways are crucial for neuronal function and plasticity.
  • Aberrant signaling in these pathways is hypothesized to contribute to schizophrenia.

Purpose of the Study:

  • To investigate the expression and phosphorylation of proteins within the MAPK- and cAMP-associated signaling pathways.
  • To compare these molecular changes in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) between individuals with schizophrenia and controls.

Main Methods:

  • Western blot analysis was performed on postmortem brain samples from elderly patients with schizophrenia and comparison groups.
  • Expression levels of specific proteins (Rap2, JNK1/2, PSD-95, Rack1, Fyn, Cdk5, NR2B) and their phosphorylation states were quantified.
  • LiCor Odyssey imaging system was used for measuring protein signal intensity.

Main Results:

  • In the ACC, decreased expression of Rap2, JNK1/2, PSD-95, and reduced phosphorylation of JNK1/2 and PSD-95 were observed in schizophrenia.
  • In the DLPFC, increased expression of Rack1, Fyn, Cdk5, and elevated phosphorylation of PSD-95 and NR2B were found in schizophrenia.
  • These findings indicate region-specific alterations in MAPK- and cAMP-associated signaling molecules in schizophrenia.

Conclusions:

  • Abnormal activity in MAPK- and cAMP-associated signaling pathways is present in frontal cortical regions in schizophrenia.
  • These molecular alterations may contribute to the neurobiological basis of schizophrenia, potentially linking to hypoglutamatergic function.
  • Intracellular signaling pathway dysregulation is implicated in the pathophysiology of schizophrenia.

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