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Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.

Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T - Mol Brain (2008)

Bottom Line: Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed.Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Frontier Technology Center, Kyoto University Graduate School of Medicine, Japan. yamasaki@kuhp.kyoto-u.ac.jp

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 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.

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Immature DG of Alpha-CaMKII+/- Mice. (A) Cells proliferate in the subgranular layer (SGL), and migrate and differentiate into mature neurons in the granular layer (GL) in the adult hippocampus. Each stage of the neuronal development has cell markers and specific morphological and physiological properties. In the DG of alpha-CaMKII+/- mice, the number of cells expressing Polysialic acid-NCAM (PSA-NCAM), a marker for late-stage progenitor cells and immature neurons, and calretinin, a marker for immature neurons, was dramatically increased, whereas the amount of calbindin, a marker for mature neurons in the DG, -positive cells was markedly reduced. Electrophysiological study of the DG neurons showed that input resistance was high and the number of spikes during sustained depolarization was decreased in mutant mice. Furthermore, morphological analysis revealed that dendritic branching and length were decreased in the mutant DG. Collectively, the mutant DG granule cells had many features that are characteristic of immature DG neurons. Red arrows represent the specific changes in the DG of alpha-CaMKII+/- mice. (B) A schematic model of gene-to-behavior pathways in alpha-CaMKII+/- mice. Alpha-CaMKII deficiency leads multiple abnormal gene expression and signal transduction, which causes "immature DG" and impaired function of hippocampus and other brain regions, resulting in abnormal behaviors of alpha-CaMKII+/- mice. Based on the finding that expression changes of genes related to neurogenesis and neural maturation/migration, including calbindin, in hippocampus is associated with higher incidence of schizophrenic patients, "Immature DG" and its equivalent hippocampal functional abnormalities may serve as a promising candidate endophenotype of psychiatric disorders, such as schizophrenia and bipolar disorders.
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Figure 6: Immature DG of Alpha-CaMKII+/- Mice. (A) Cells proliferate in the subgranular layer (SGL), and migrate and differentiate into mature neurons in the granular layer (GL) in the adult hippocampus. Each stage of the neuronal development has cell markers and specific morphological and physiological properties. In the DG of alpha-CaMKII+/- mice, the number of cells expressing Polysialic acid-NCAM (PSA-NCAM), a marker for late-stage progenitor cells and immature neurons, and calretinin, a marker for immature neurons, was dramatically increased, whereas the amount of calbindin, a marker for mature neurons in the DG, -positive cells was markedly reduced. Electrophysiological study of the DG neurons showed that input resistance was high and the number of spikes during sustained depolarization was decreased in mutant mice. Furthermore, morphological analysis revealed that dendritic branching and length were decreased in the mutant DG. Collectively, the mutant DG granule cells had many features that are characteristic of immature DG neurons. Red arrows represent the specific changes in the DG of alpha-CaMKII+/- mice. (B) A schematic model of gene-to-behavior pathways in alpha-CaMKII+/- mice. Alpha-CaMKII deficiency leads multiple abnormal gene expression and signal transduction, which causes "immature DG" and impaired function of hippocampus and other brain regions, resulting in abnormal behaviors of alpha-CaMKII+/- mice. Based on the finding that expression changes of genes related to neurogenesis and neural maturation/migration, including calbindin, in hippocampus is associated with higher incidence of schizophrenic patients, "Immature DG" and its equivalent hippocampal functional abnormalities may serve as a promising candidate endophenotype of psychiatric disorders, such as schizophrenia and bipolar disorders.

Mentions: In summary, we show that alpha-CaMKII heterozygous knockout mice have dysregulated behaviors, including a severe working memory deficit and an exaggerated infradian rhythm. Most neurons in the mutant DG failed to mature, with differential expressions of more than 2000 genes in hippocampus. Transcriptome analysis of human post-mortem brain revealed that biomarkers derived from mutants classified individuals into two clusters, one of which had higher susceptibility to schizophrenia and differentially expressed genes related to neural development, including calbindin, a marker for mature DG neurons. Taken together, we propose "immature DG" as a candidate endophenotype of schizophrenia and other psychiatric disorders (Figure 6).


Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.

Yamasaki N, Maekawa M, Kobayashi K, Kajii Y, Maeda J, Soma M, Takao K, Tanda K, Ohira K, Toyama K, Kanzaki K, Fukunaga K, Sudo Y, Ichinose H, Ikeda M, Iwata N, Ozaki N, Suzuki H, Higuchi M, Suhara T, Yuasa S, Miyakawa T - Mol Brain (2008)

Immature DG of Alpha-CaMKII+/- Mice. (A) Cells proliferate in the subgranular layer (SGL), and migrate and differentiate into mature neurons in the granular layer (GL) in the adult hippocampus. Each stage of the neuronal development has cell markers and specific morphological and physiological properties. In the DG of alpha-CaMKII+/- mice, the number of cells expressing Polysialic acid-NCAM (PSA-NCAM), a marker for late-stage progenitor cells and immature neurons, and calretinin, a marker for immature neurons, was dramatically increased, whereas the amount of calbindin, a marker for mature neurons in the DG, -positive cells was markedly reduced. Electrophysiological study of the DG neurons showed that input resistance was high and the number of spikes during sustained depolarization was decreased in mutant mice. Furthermore, morphological analysis revealed that dendritic branching and length were decreased in the mutant DG. Collectively, the mutant DG granule cells had many features that are characteristic of immature DG neurons. Red arrows represent the specific changes in the DG of alpha-CaMKII+/- mice. (B) A schematic model of gene-to-behavior pathways in alpha-CaMKII+/- mice. Alpha-CaMKII deficiency leads multiple abnormal gene expression and signal transduction, which causes "immature DG" and impaired function of hippocampus and other brain regions, resulting in abnormal behaviors of alpha-CaMKII+/- mice. Based on the finding that expression changes of genes related to neurogenesis and neural maturation/migration, including calbindin, in hippocampus is associated with higher incidence of schizophrenic patients, "Immature DG" and its equivalent hippocampal functional abnormalities may serve as a promising candidate endophenotype of psychiatric disorders, such as schizophrenia and bipolar disorders.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: Immature DG of Alpha-CaMKII+/- Mice. (A) Cells proliferate in the subgranular layer (SGL), and migrate and differentiate into mature neurons in the granular layer (GL) in the adult hippocampus. Each stage of the neuronal development has cell markers and specific morphological and physiological properties. In the DG of alpha-CaMKII+/- mice, the number of cells expressing Polysialic acid-NCAM (PSA-NCAM), a marker for late-stage progenitor cells and immature neurons, and calretinin, a marker for immature neurons, was dramatically increased, whereas the amount of calbindin, a marker for mature neurons in the DG, -positive cells was markedly reduced. Electrophysiological study of the DG neurons showed that input resistance was high and the number of spikes during sustained depolarization was decreased in mutant mice. Furthermore, morphological analysis revealed that dendritic branching and length were decreased in the mutant DG. Collectively, the mutant DG granule cells had many features that are characteristic of immature DG neurons. Red arrows represent the specific changes in the DG of alpha-CaMKII+/- mice. (B) A schematic model of gene-to-behavior pathways in alpha-CaMKII+/- mice. Alpha-CaMKII deficiency leads multiple abnormal gene expression and signal transduction, which causes "immature DG" and impaired function of hippocampus and other brain regions, resulting in abnormal behaviors of alpha-CaMKII+/- mice. Based on the finding that expression changes of genes related to neurogenesis and neural maturation/migration, including calbindin, in hippocampus is associated with higher incidence of schizophrenic patients, "Immature DG" and its equivalent hippocampal functional abnormalities may serve as a promising candidate endophenotype of psychiatric disorders, such as schizophrenia and bipolar disorders.
Mentions: In summary, we show that alpha-CaMKII heterozygous knockout mice have dysregulated behaviors, including a severe working memory deficit and an exaggerated infradian rhythm. Most neurons in the mutant DG failed to mature, with differential expressions of more than 2000 genes in hippocampus. Transcriptome analysis of human post-mortem brain revealed that biomarkers derived from mutants classified individuals into two clusters, one of which had higher susceptibility to schizophrenia and differentially expressed genes related to neural development, including calbindin, a marker for mature DG neurons. Taken together, we propose "immature DG" as a candidate endophenotype of schizophrenia and other psychiatric disorders (Figure 6).

Bottom Line: Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed.Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Frontier Technology Center, Kyoto University Graduate School of Medicine, Japan. yamasaki@kuhp.kyoto-u.ac.jp

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 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.

Show MeSH
Related in: MedlinePlus