title: Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia.
abstract: Recent genetic linkage analysis has shown that LRRTM1 (Leucine rich repeat transmembrane neuronal 1) is associated with schizophrenia. Here, we characterized Lrrtm1 knockout mice behaviorally and morphologically. Systematic behavioral analysis revealed reduced locomotor activity in the early dark phase, altered behavioral responses to novel environments (open-field box, light-dark box, elevated plus maze, and hole board), avoidance of approach to large inanimate objects, social discrimination deficit, and spatial memory deficit. Upon administration of the NMDA receptor antagonist MK-801, Lrrtm1 knockout mice showed both locomotive activities in the open-field box and responses to the inanimate object that were distinct from those of wild-type mice, suggesting that altered glutamatergic transmission underlay the behavioral abnormalities. Furthermore, administration of a selective serotonin reuptake inhibitor (fluoxetine) rescued the abnormality in the elevated plus maze. Morphologically, the brains of Lrrtm1 knockout mice showed reduction in total hippocampus size and reduced synaptic density. The hippocampal synapses were characterized by elongated spines and diffusely distributed synaptic vesicles, indicating the role of Lrrtm1 in maintaining synaptic integrity. Although the pharmacobehavioral phenotype was not entirely characteristic of those of schizophrenia model animals, the impaired cognitive function may warrant the further study of LRRTM1 in relevance to schizophrenia.
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Takashima
authors.forename: Yuri S
authors.initials: YS
authors.lastname: Odaka
authors.forename: Kazuto
authors.initials: K
authors.lastname: Sakoori
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Morimura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004777:Environment; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology* / Q000648:ultrastructure; D008565:Membrane Proteins; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine; D016291:Dizocilpine Maleate; D005473:Fluoxetine; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D017367:Selective Serotonin Reuptake Inhibitors; C561490:LRRTM1 protein, mouse