Lithium-related genetics of bipolar disorder.
Lithium is a potent prophylactic medication and mood stabilizer in bipolar disorder. However, clinical outcome is variable, and its therapeutic effect manifests after a period of chronic treatment, implying a progressive and complex biological response process. Signal transduction systems known to be perturbed by lithium involve phosphoinositide (PI) turnover, activation of the Wnt pathway via inhibition of glycogen synthase kinase-3beta (GSK-3beta), and a growth factor-induced, Akt-mediated signalling that promotes cell survival. These pathways, acting in synergy, probably prompt the amplification of lithium signal causing such immense impact on the neuronal network. The sequencing of the human genome presents an unparallelled opportunity to uncover the full molecular repertoire involved in lithium action. Interrogation of high-resolution expression microarrays and protein profiles represents a strategy that should help accomplish this goal. A recent microarray analysis on lithium-treated versus untreated PC12 cells identified multiple differentially altered transcripts. Lithium-perturbed genes, particularly those that map to susceptibility regions, could be candidate risk-conferring factors for mood disorders. Transcript and protein profiling in patients could reveal a lithium fingerprint for responsiveness or nonresponsiveness, and a signature motif that may be diagnostic of a specific phenotype. Similarly, lithium-sensitive gene products could provide a new generation of pharmacological targets.
Detera-Wadleigh
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National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD 20892-4094, USA. sevilla@helix.nih.gov
D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008094:Lithium / Q000494:pharmacology* / Q000627:therapeutic use; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects; D011110:Polymorphism, Genetic; D011493:Protein Kinase C / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D019269:Phosphatidylinositol 4,5-Diphosphate; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D008094:Lithium; D038341:Glycogen Synthase Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase