Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression

Although the etiology of schizophrenia remains unknown, diverse neuropathological evidence suggests a disorder of synaptic connectivity. Apoptosis is a form of cell death that helps determine synaptic circuitry during neurodevelopment and altered regulation of apoptosis has been implicated in schizophrenia. Prostate apoptosis response-4 (Par-4) is an upstream regulator of apoptosis preferentially localized to synapses. Brain Par-4 levels are upregulated in response to pro-apoptotic stimuli in rodent models and in patients with classic neurodegenerative diseases. Recently, Par-4 was also found to form a complex with the dopamine D2 receptor (D2DR) in competition with the calcium-binding protein calmodulin, implicating Par-4 as an important regulatory component in normal dopamine signaling. Interestingly, mutant mice with disrupted Par-4/D2DR interaction demonstrated depressive-like behaviors, suggesting a potential role for Par-4 in both depression and schizophrenia. In this study, Par-4, D2DR and calmodulin protein levels were measured using semiquantitative Western blotting in postmortem temporal cortex in subjects with schizophrenia, major depression and bipolar disorder. Compared to normal controls, mean Par-4 levels appeared slightly lower in schizophrenia and bipolar disorder. However, in major depression, Par-4 was decreased by 67% compared to normal controls. No differences were found between any groups for calmodulin or for the D2DR 48 kDa band. The D2DR 98 kDa band was lower by 50% in the schizophrenia compared to control groups. Changes in the Par-4/D2DR signaling pathway represent a novel mechanism that may link apoptotic and dopamine signaling pathways in major depression and schizophrenia

Neurosteroid Levels in the Orbital Frontal Cortex of Subjects With PTSD and Controls: A Preliminary Report

Background Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD ( n  = 18) and controls ( n  = 35). Methods Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography-tandem mass spectrometry. Results Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( p  = 0.03) compared to control males, and females with PTSD had significantly increased levels of pregnenolone ( p  = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( t 46  = 2.37, p  = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( t 46  = −2.25, p  = 0.03) relative to control females. Conclusions To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC