Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims.
BACKGROUND
Depression is a major public health problem. Despite many years of research, the molecular mechanisms associated with depression remain unclear. Rap-1, activated in response to many extracellular stimuli, is one of the major substrates of protein kinase A, which participates in myriad physiologic functions in the brain, including cell survival and synaptic plasticity. Rap-1 is also activated directly by cyclic adenosine monophosphate through Epac, and thus participates in mediating physiologic functions independent of protein kinase A.


OBJECTIVE
To examine whether the pathogenesis of depression is associated with altered activation and expression of Rap-1, as well as expression of Epac, in depressed suicide victims.


METHODS
Postmortem study.


METHODS
Tissues were obtained from the Lenhossek Human Brain Program, Semmelweis University, Budapest, Hungary, and the Brain Collection Program of the Maryland Psychiatric Research Center, Baltimore.


METHODS
Postmortem brains of 28 depressed suicide victims and 28 nonpsychiatric control subjects.


METHODS
Examination of brain tissues.


METHODS
Rap-1 activation as well as messenger RNA and protein levels of Rap-1 and Epac in prefrontal cortex, hippocampus, and cerebellum.


RESULTS
Rap-1 activation was significantly reduced (P<.001) in prefrontal cortex and hippocampus in the suicide group. This was associated with significant reductions in Rap-1 messenger RNA and protein levels (P<.001). In contrast, protein level of only Epac-2 (P<.001) but not Epac-1 (P = .89) was significantly increased in prefrontal cortex and hippocampus of these subjects. These changes were present whether the 2 cohorts were analyzed together or separately. None of the measures showed any significant change in cerebellum in the suicide group.


CONCLUSIONS
Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.
Dwivedi
Yogesh
Y
Department of Psychiatry, University of Illinois at Chicago, 60612, USA. ydwivedi@psych.uic.edu
Mondal
Amal C
AC
Rizavi
Hooriyah S
HS
Faludi
Gabor
G
Palkovits
Miklos
M
Sarosi
Andrea
A
Conley
Robert R
RR
Pandey
Ghanshyam N
GN
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000235:genetics; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D003866:Depressive Disorder / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology; D017397:Prefrontal Cortex / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013405:Suicide / Q000706:statistics & numerical data*; D014018:Tissue Distribution; D020827:rap1 GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology
D012333:RNA, Messenger; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D020827:rap1 GTP-Binding Proteins; D000111:Acetylcysteine