[Approach to depressogenic genes from genetic analyses of animal models].
Human depression or mood disorder is defined as a complex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of three different animal models for depression, comparing our results with advanced database resources. We first performed quantitative trait loci (QTL) analysis on two mouse models of "despair", namely, the forced swim test (FST) and tail suspension test (TST), and detected multiple chromosomal loci that control immobility time in these tests. Since one QTL detected on mouse chromosome 11 harbors the GABA A receptor subunit genes, we tested these genes for association in human mood disorder patients. We obtained significant associations of the alpha 1 and alpha 6 subunit genes with the disease, particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosomes 11 and X that regulates immobility time in these animals. Next, we performed genome-wide expression analyses using a rat model of depression, learned helplessness (LH). We found that in the frontal cortex of LH rats, a disease implicated region, the LIM kinase 1 gene (Limk 1) showed greatest alteration, in this case down-regulation. By combining data from the QTL analysis of FST/TST and DNA microarray analysis of mouse frontal cortex, we identified adenylyl cyclase-associated CAP protein 1 (Cap 1) as another candidate gene for depression susceptibility. Both Limk 1 and Cap 1 are key players in the modulation of actin G-F conversion. In summary, our current study using animal models suggests disturbances of GABAergic neurotransmission and actin turnover as potential pathophysiologies for mood disorder.
Yoshikawa
Takeo
T
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute.
D000199:Actins / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003598:Cytoskeletal Proteins; D003863:Depression / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006380:Helplessness, Learned; D019417:Hindlimb Suspension; D006801:Humans; D054461:Lim Kinases; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology; D013550:Swimming
D000199:Actins; D000928:Antidepressive Agents; C081782:Cap1 protein, rat; D003598:Cytoskeletal Proteins; D011506:Proteins; D011963:Receptors, GABA-A; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515893:Limk1 protein, mouse; C515894:Limk1 protein, rat