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

Abstract

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.

Allopregnanolone as a mediator of affective switching in reproductive mood disorders

“…ALLO administered during stress prevents the onset of depression-like behavior in rodents and preserves neurogenesis in the hippocampus (Evans et al 2012). ALLO also exerts neuroprotective effects by reducing the expression of pro-apoptotic proteins and apoptotic DNA fragmentation (Djebaili et al 2005; Sayeed et al 2009), thereby reducing the cell death and gliosis associated with depression (Glantz et al 2010; Shelton et al 2011). Neuroprotection is mediated by immune regulation in depression (Licinio and Wong 1999), and ALLO reduces the expression of the pro-inflammatory cytokine TNF-α (He et al 2004), which is elevated in individuals with major depression (Dowlati et al 2010).…”

Novel Dopamine D2 Receptor Signaling through Proteins Interacting with the Third Cytoplasmic Loop

“…In addition, disruption of Par-4 and D2 receptor interaction in transgenic mice expressing a Par-4 mutant promoted an increase in depression-like behaviors in forced swim and tail suspension tests [31]. Par-4 expression levels in significantly depressed or schizophrenic patients are also significantly decreased compared to normal controls [32]. Taken together, Ca 2+ /CaM competition with Par-4 on the D2 receptor is likely important in regulating the apoptotic effects of Par-4 on cells that express D2 receptor.…”

Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy

“…Arent et al [] hypothesized that increased HDAC activity may be causal in BPD and the antimanic effects of HDAC inhibitors, sodium butyrate (NaBu) or VPA, were found after microinjection into the amygdala, striatum, and prefrontal cortex. Deficits in dopamine are also associated with mood disorders [Nader et al, ] with levels of prostate apoptosis response 4 ( Par‐4 ), a regulatory component of DA D2 receptor activity, being decreased in the temporal cortex of patients with BPD and major depression [Glantz et al, ]. Chronic VPA treatment up‐regulated transcription of Par‐4 gene resulting in altered D2 receptor signaling [Lee et al, ].…”