Alterations in phosphorylated cAMP response element-binding protein (pCREB) signaling: an endophenotype of lithium-responsive bipolar disorder?
OBJECTIVE
Abnormalities of signal transduction are considered among the susceptibility factors for bipolar disorder (BD). These include changes in G-protein-mediated signaling and subsequent modification of gene expression via transcription factors such as cAMP response element-binding protein (CREB).


METHODS
We investigated levels of CREB in lymphoblasts from patients with BD, all responders to lithium prophylaxis (n = 13), and healthy control subjects (n = 15). Phosphorylated CREB (pCREB) was measured by immunoblotting in subjects with BD (n = 15) as well as in their affected (n = 17) and unaffected (n = 18) relatives, and healthy controls (n = 16).


RESULTS
Basal CREB levels were comparable in patients and control subjects and were not changed by lithium treatment. pCREB levels were increased in both patients and their relatives compared to controls (p = 0.003). Forskolin stimulation led to a 24% increase in pCREB levels in cells from healthy subjects (p = 0.002) but not in the other three groups. When using basal and stimulated pCREB levels as a biochemical phenotype in a preliminary linkage study, we found the strongest support for linkage in regions largely overlapping with those showing linkage with the clinical phenotype (3p, 6p, 16p, 17q, 19q, and 21q).


CONCLUSIONS
Abnormal pCREB signaling could be considered a biochemical phenotype for lithium-responsive BD.
Department of Psychiatry, Dalhousie University, Halifax, NS.
Martin
M
Alda
Li
L
Shao
Jun-Feng
JF
Wang
Catalina
C
Lopez de Lara
Iris
I
Jaitovich-Groisman
Veronique
V
Lebel
Xiujun
X
Sun
Anne
A
Duffy
Paul
P
Grof
Guy A
GA
Rouleau
Gustavo
G
Turecki
L Trevor
LT
Young
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005190:Family; D005260:Female; D005838:Genotype; D006801:Humans; D018021:Lithium Chloride / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects
D000276:Adjuvants, Immunologic; D018692:Antimanic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D005576:Colforsin; D018021:Lithium Chloride
bipolar disorder; cAMP response element-binding protein (CREB); cAMP response element-binding protein (CREB) phosphorylation; genetic linkage; lithium response