Abstract
Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours 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. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose 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.
Highlights
Elucidating the neural and genetic factors underlying psychiatric illness is hampered by the current methods of clinical diagnosis [1]
Severe working memory deficits and exaggerated infradian rhythm in alpha-CaMKII+/- mice Alpha-CaMKII+/- mice have decreased anxiety-like behavior, increased aggressive behavior [20], and deficits in long-term memory and the establishment of permanent
We compared the gene expression profile between the schizophrenic patients in the schizophrenia-enriched cluster and the controls with no major psychiatric diagnosis in the control-enriched cluster, and found 26 differentiallyexpressed probes in the schizophrenic patients. Almost half of these differentially-expressed genes are involved in neurogenesis or neuronal migration/maturation, including calbindin, a maker for mature neurons in dentate gyrus (DG) (Figure 5B, Table 1, Additional file 1, Figure S12 and S13, and Additional file 2, Table S3 and S4). These results indicate that schizophrenia subgroup could be classified using the biomarkers derived from the alpha-CaMKII+/- mice, and that the functional alterations in the hippocampus could be a potential intermediate phenotype for this schizophrenia subgroup, consistent with proposals that the hippocampus is central to the pathophysiology of schizophrenia [31,32]
Summary
Elucidating the neural and genetic factors underlying psychiatric illness is hampered by the current methods of clinical diagnosis [1]. Schizophrenia is significantly associated with a variation in the 8p21.3 gene, PPP3CC, which encodes the CNA gamma subunit of calcineurin [9,10,11] Based on these findings, we speculated that we could efficiently obtain a mouse model of psychiatric disorders by applying a comprehensive behavioral test battery [12] to various strains of mice bearing mutations of the genes encoding the molecules involved in CN signaling pathways or CN related neural mechanisms [13]. The only mutant mouse strain that exhibited a significant working memory deficit, a proposed functional endophenotype of schizophrenia and other psychiatric disorders [15], was heterozygous for a null mutation of the alpha-isoform of CaMKII (alpha-CaMKII+/-) (Figure 1A and 1B). CaMKII is situated downstream of CN in a model [19]
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