Immature dentate gyrus as a candidate endophenotype of psychiatric disorders

Despite massive research efforts, the exact pathogenesis and pathophysiology of psychiatric disorders, such as schizophrenia and bipolar disorder, remain largely unknown. Animal models can serve as essential tools for investigating the etiology and treatment of such disorders. Some mutant mouse strains were found to exhibit behavioral abnormalities reminiscent of human psychiatric disorders. Here we outline our unique approach of extrapolating findings in mice to humans, and present studies on alpha-CaMKII heterozygous knockout (alpha-CaMKII HKO) mice as examples. Alpha-CaMKII HKO mice have profoundly dysregulated behavior and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. By conducting a series of experiments, we discovered that almost all the neurons in the mutant DG were very similar to the immature DG neurons of normal rodents. In other words, alpha-CaMKII HKO mice have an "immature DG". We proposed that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.