Biological basis of schizophrenia
Relationships between genes and behavior
I have been trying to find animal model of psychiatric disorders by using, what we call, a comprehensive behavioral tests battery on mutant mice. During these 17 years, I have looked at more nearly 140 strains of mutant mice, like knockout mice or transgenic mice. So far we have identified several different mice models of schizophrenia/bipolar disorders. Among them are forebrain calcineurin knockout mice and alpha-CaMKII HKO mice (Zeng et al., Cell, 2001; Miyakawa et al., PNAS, 2003; Gerber et al., PNAS, 2003; Yamasaki et al., Molecular Brain, 2008). We are also trying to find what's going on in the brains of those mice model of psychiatric disorders using a variety of techniques such as gene ship analysis, proteome analysis, neural activity mapping using c-Fos or Arc, electrophysiological analyses and etc.
Sar far, we have found a remarkable phenotype in the hippocampus of the brain, which I named, "immature Dentate Gyrus (=iDG)" (Yamasaki et al., Molecular Brain, 2008; Matsuo et al., Frontiers in Behavioral Neuroscience, 2009). In iDG of those animals, most of the DG neurons fail to mature and stay immature, even after the mice become adults.
We realized that this iDG phenotype is quite common among the mice showing hyperactivity and working memory deficit.
Interestingly, chronic treatment of Fluoxetine, a SSRI type of anti-depressants, can also cause iDG in normal B6 mice. We call it "dematuration" (Kobayashi et al, PNAS, 2010).
Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory