Intrauterine environment-genome interaction and children's development (4): Brain-behavior phenotypying of genetically-engineered mice using a comprehensive behavioral test battery on research of neuropsychiatric 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+/-) mice as examples. Alpha-CaMKII+/- 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+/- 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. The impact of a large-scale mouse phenotyping on studies of psychiatric disorders and the potential utility of an "animal-model-array" of psychiatric disorders for the development of suitable therapeutic agents is also discussed.

[1]  T. Miyakawa,et al.  Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia , 2008, Molecular Brain.

[2]  K. Nakayama,et al.  Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. , 2008, Human molecular genetics.

[3]  Ryoichiro Kageyama,et al.  Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain , 2008, Nature Neuroscience.

[4]  Ryuichi Nakajima,et al.  Comprehensive behavioral phenotyping of calpastatin-knockout mice , 2008, Molecular Brain.

[5]  K. Fukunaga,et al.  Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders , 2008, European Psychiatry.

[6]  D. Murphy,et al.  Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions , 2008, Behavioural pharmacology.

[7]  R. Hashimoto,et al.  Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. , 2008, Biochemical and biophysical research communications.

[8]  T. Miyakawa,et al.  Mice Lacking the kf-1 Gene Exhibit Increased Anxiety- but not Despair-Like Behavior , 2008, Frontiers in behavioral neuroscience.

[9]  Lisa M. Wiedholz,et al.  Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and ‘schizophrenia-related’ behaviors , 2008, Molecular Psychiatry.

[10]  A. Wynshaw-Boris,et al.  Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. , 2008, Human molecular genetics.

[11]  R. Straub,et al.  Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients , 2008, Schizophrenia Research.

[12]  J. Waddington,et al.  Susceptibility genes for schizophrenia: Characterisation of mutant mouse models at the level of phenotypic behaviour , 2007, Neuroscience & Biobehavioral Reviews.

[13]  Alcino J. Silva,et al.  Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice , 2007, Proceedings of the National Academy of Sciences.

[14]  R. Kesner.  Behavioral functions of the CA3 subregion of the hippocampus. , 2007, Learning & memory.

[15]  J. Guzowski,et al.  Using immediate-early genes to map hippocampal subregional functions. , 2007, Learning & memory.

[16]  P. Schofield,et al.  Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia , 2007, Genes, brain, and behavior.

[17]  T. Miyakawa,et al.  Impact of brain-behavior phenotypying of genetically-engineered mice on research of neuropsychiatric disorders , 2007, Neuroscience Research.

[18]  S. Faraone,et al.  More evidence supports the association of PPP3CC with schizophrenia , 2007, Molecular Psychiatry.

[19]  Susumu Tonegawa,et al.  Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia , 2007, Proceedings of the National Academy of Sciences.

[20]  J. Rawlins,et al.  Impaired spatial working memory but spared spatial reference memory following functional loss of NMDA receptors in the dentate gyrus , 2007, The European journal of neuroscience.

[21]  Wolfgang Wurst,et al.  A Mouse for All Reasons , 2007, Cell.

[22]  T. Miyakawa,et al.  Investigating Gene‐to‐Behavior Pathways in Psychiatric Disorders , 2006, Annals of the New York Academy of Sciences.

[23]  Chang-Gyu Hahn,et al.  Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. , 2006, Human molecular genetics.

[24]  J. Gogos,et al.  Modeling Madness in Mice: One Piece at a Time , 2006, Neuron.

[25]  J. Fell,et al.  Memory formation by neuronal synchronization , 2006, Brain Research Reviews.

[26]  D. Weinberger,et al.  Genetic Mouse Models of Schizophrenia: From Hypothesis-Based To Susceptibility Gene-Based Models , 2006, Biological Psychiatry.

[27]  T. Miyakawa,et al.  Schizophrenia-Relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? , 2006, Biological Psychiatry.

[28]  Xin Gao,et al.  NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21 , 2006, Nature.

[29]  A. Epstein,et al.  Knocking‐down the NMDAR1 subunit in a limited amount of neurons in the rat hippocampus impairs learning , 2006, Journal of neurochemistry.

[30]  Hiroko Koike,et al.  Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  I. Gottesman,et al.  Psychiatric endophenotypes and the development of valid animal models , 2006, Genes, brain, and behavior.

[32]  Michael C O'Donovan,et al.  Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. , 2005, Human molecular genetics.

[33]  J. Crawley.  Designing mouse behavioral tasks relevant to autistic-like behaviors. , 2004, Mental retardation and developmental disabilities research reviews.

[34]  K. Giese,et al.  Mouse Genetic Approaches to Investigating Calcium/Calmodulin-Dependent Protein Kinase II Function in Plasticity and Cognition , 2004, The Journal of Neuroscience.

[35]  N. Freimer,et al.  Why genetic investigation of psychiatric disorders is so difficult. , 2004, Current opinion in genetics & development.

[36]  Daniel R Weinberger,et al.  Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. , 2004, Archives of general psychiatry.

[37]  Raquel E Gur,et al.  Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. , 2004, The Journal of clinical investigation.

[38]  Hongkui Zeng,et al.  Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Susumu Tonegawa,et al.  Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  W. Wetsel,et al.  Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice , 2003, Neuroscience.

[41]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[42]  P. H. Seeburg,et al.  Spatial memory dissociations in mice lacking GluR1 , 2002, Nature Neuroscience.

[43]  Hongkui Zeng,et al.  Forebrain-Specific Calcineurin Knockout Selectively Impairs Bidirectional Synaptic Plasticity and Working/Episodic-like Memory , 2001, Cell.

[44]  R. Gainetdinov,et al.  Genetic animal models: focus on schizophrenia , 2001, Trends in Neurosciences.

[45]  D. Winder,et al.  Plasticity and behavior New genetic techniques to address multiple forms and functions , 2001, Physiology & Behavior.

[46]  J. Wess,et al.  Hyperactivity and Intact Hippocampus-Dependent Learning in Mice Lacking the M1 Muscarinic Acetylcholine Receptor , 2001, The Journal of Neuroscience.

[47]  C. Lazarus,et al.  Cognitive Performances and Locomotor Activity Following Dentate Granule Cell Damage in Rats: Role of Lesion Extent and Type of Memory Tested , 2001, Neurobiology of Learning and Memory.

[48]  J. David Sweatt,et al.  Roles of serine/threonine phosphatases in hippocampel synaptic plasticity , 2001, Nature Reviews Neuroscience.

[49]  T. Yagi,et al.  Differential effect of Fyn tyrosine kinase deletion on offensive and defensive aggression , 2001, Behavioural Brain Research.

[50]  A. Yamanaka,et al.  Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean , 2001, Nature.

[51]  J. T. Erichsen,et al.  Using Fos Imaging in the Rat to Reveal the Anatomical Extent of the Disruptive Effects of Fornix Lesions , 2000, The Journal of Neuroscience.

[52]  Martin S. Taylor,et al.  Disruption of two novel genes by a translocation co-segregating with schizophrenia. , 2000, Human molecular genetics.

[53]  Marc G Caron,et al.  Mice with Reduced NMDA Receptor Expression Display Behaviors Related to Schizophrenia , 1999, Cell.

[54]  E D Levin,et al.  Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. , 1999, Science.

[55]  H. Prior,et al.  Dissociation of spatial reference memory, spatial working memory, and hippocampal mossy fiber distribution in two rat strains differing in emotionality , 1997, Behavioural Brain Research.

[56]  R. Nicoll,et al.  Contrasting properties of two forms of long-term potentiation in the hippocampus , 1995, Nature.

[57]  T. Yagi,et al.  Enhanced susceptibility of audiogenic seizures in Fyn-kinase deficient mice. , 1995, Brain research. Molecular brain research.

[58]  T. Yagi,et al.  Increased fearfulness of Fyn tyrosine kinase deficient mice. , 1994, Brain research. Molecular brain research.

[59]  Alcino J. Silva,et al.  Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[60]  Alcino J. Silva,et al.  Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[61]  Wim E Crusio,et al.  Hippocampal mossy fibers and radial-maze learning in the mouse: A correlation with spatial working memory but not with non-spatial reference memory , 1990, Neuroscience.

[62]  A. Clarke,et al.  Germ line transmission and expression of a corrected HPRT gene produced by gene targeting in embryonic stem cells , 1989, Cell.

[63]  P S Goldman-Rakic,et al.  Activation of the hippocampus and dentate gyrus by working-memory: a 2- deoxyglucose study of behaving rhesus monkeys , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[64]  K. Kendler,et al.  The dystrobrevin-binding protein 1 gene: features and networks , 2009, Molecular Psychiatry.

[65]  R. Kesner.  A behavioral analysis of dentate gyrus function. , 2007, Progress in brain research.

[66]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[67]  J. Crawley,et al.  Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components , 2001, Hippocampus.

[68]  G. Xavier,et al.  Dentate gyrus‐selective colchicine lesion and disruption of performance in spatial tasks: Difficulties in “place strategy” because of a lack of flexibility in the use of environmental cues? , 1999, Hippocampus.

[69]  P. Greengard,et al.  Beyond the Dopamine Receptor: Review the DARPP-32/Protein Phosphatase-1 Cascade , 1999 .

[70]  P. Goldman-Rakic.  Working memory dysfunction in schizophrenia. , 1994, The Journal of neuropsychiatry and clinical neurosciences.