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.

APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission

“…So far, the binding of APLP1 and APLP2 has been reported for the X11␤/MINT2 isoform using a yeast two-hybrid assay (Tomita et al, 1999). Here, we validated the interaction of APLP1 and APLP2 to all members of the X11/MINT family via coimmunoprecipitations (Fig.…”

“…Single-KO mice of other SAMs like LRRTM1, LRRTM3, or LRRTM4; SynCAM1; or Neuroligin1 show decreased spine numbers already at an early age (between 6 and 23 weeks of age; Takashima et al, 2011;Kwon et al, 2012;Siddiqui et al, 2013;Doengi et al, 2016;Um et al, 2016), indicating different functions in synapse formation, probably more in early stages of initial synapse formation, whereas the members of the APP family might affect more specific mechanisms of structural plasticity in adult stages. Collectively, our findings show that APLP1 has a unique function among the APP family members (Fig.…”

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

“…[47][48][49][50] Among LRR proteins, LRFNs form a family of transmembrane cell adhesion molecules that promote changes in neuronal morphology, dendritic outgrowth and synapse formation. [51][52][53] It was further demonstrated that LRFNs form complexes with NMDARs, and promote the specialization of excitatory synapses.…”

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

“…Takashima et al ( 2011 ), but not Voikar et al ( 2013 ), found that Lrrtm1 -knockout mice demonstrate reduced spontaneous locomotor activity, defi cits in spatial memory, and increased freezing (an index of fear memory), whereas only Voikar et al ( 2013 ) observed that Lrrtm1 -knockout mice avoid small enclosures. However, in both studies it is concluded that Lrrtm1-knockout mice demonstrate a reduced ability to adjust or adapt to novel or stressful environments Voikar et al 2013 ).…”