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

Glantz, Leisa A.; Gilmore, John H.; Overstreet, David H.; Salimi, Kayvon; Lieberman, Jeffrey A.; Jarskog, L. Fredrik

doi:10.1016/j.schres.2009.12.027

« Previous Next »Schizophrenia Research
Volume 118, Issue 1 , Pages 292-299, May 2010

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

Leisa A. Glantz
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
John H. Gilmore
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
David H. Overstreet
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Kayvon Salimi
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Jeffrey A. Lieberman
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
L. Fredrik Jarskog
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
- Corresponding author. NYSPI/Columbia University, 1051 Riverside Drive, Unit #42, New York, NY 10032, USA. Tel.: +1 212 543 6711; fax: +1 212 543 1350.

Received 4 September 2009; received in revised form 18 December 2009; accepted 21 December 2009. published online 13 January 2010.

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 48kDa band. The D2DR 98kDa 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.