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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.

Impaired Cognitive Function and Altered Hippocampal Synapse Morphology in Mice Lacking Lrrtm1, a Gene Associated with Schizophrenia