Impairment of social and emotional behaviors in Cadm1-knockout mice

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Abstract

Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, mediates synaptic cell adhesion. Missense mutations in the CADM1 gene have been identified in autism spectrum disorder (ASD) patients. In the present study, we examined emotional behaviors, social behaviors and motor performances in Cadm1-knockout (KO) mice. Cadm1-KO mice showed increased anxiety-related behavior in open-field and light–dark transition tests. Social behaviors of Cadm1-KO mice were impaired in social interaction, resident-intruder and social memory/recognition tests. Furthermore, motor coordination and gait of Cadm1-KO mice were impaired in rotarod and footprint tests. Our study demonstrates that CADM1 plays roles in regulating emotional behaviors, social behaviors and motor performances, and that CADM1 has important implications for psychiatric disorders with disruptions in social behavior, such as autism.

Introduction

CADM1 (previously known as TSLC1, IGSF4, SgIGSF, SynCAM1, Necl2, RA175), a member of the immunoglobulin (Ig) superfamily, is a synaptic cell adhesion molecule [1], [2], [3], [4]. CADM1 contains three extracellular Ig-like domains followed by a single transmembrane region and a short cytosolic sequence that interacts with PDZ (postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1) domains of synaptic scaffolding molecules [1]. CADM1 is required for synapse formation and maturation of presynaptic terminals [1], [2], [3], [4].

Recently, we identified two missense mutations, C739A (H246N) and A755C (Y251S), in the CADM1 gene of male Caucasian autism spectrum disorder (ASD) patients and their family members [5]. Both mutations are located in the third Ig domain of CADM1, which is essential for cell adhesive trans-interaction [1]. The mutated CADM1 exhibited defective trafficking to the cell surface and more susceptibility to the cleavage and/or degradation. From these results, we suppose that phenotypes in ASD patients might partly correlate with impaired synaptogenesis induced by these mutations.

In the present study, to assess the roles of endogenous CADM1 in behavioral functions, we examined emotional behaviors, social behaviors and motor performances in Cadm1-KO mice. We used Cadm1-KO mice on a C57BL/6J background.

Section snippets

Animals

Cadm1-KO mice [6], heterozygous mice and wild-type mice were obtained from heterozygous intercrosses on the C57BL/6J background for 10 generations. All behavioral studies were performed between 13:00 and 17:00 using Cadm1-KO, heterozygous and their littermate wild-type male mice. Animals had free access to food and water under the condition of 12-h light–dark cycle (22 ± 2 °C, 40–70% humidity, light on between 7:30 and 19:30). Experimental protocols used throughout the study were approved by an

Results

We tested the mice for anxiety-related behaviors using the open field, light–dark transition, and elevated plus-maze tests. The Cadm1-KO mice showed reduced center time in the open-field test (Fig. 1A) and less time in the light box of the light–dark test (Fig. 1B). Because the total distance in the open field or light–dark test did not show a significant genotype-dependent difference, the lessened time in the center or in the light box was not attributable to locomotor impairment of Cadm1-KO

Discussion

In the present study, Cadm1-KO mice exhibited increased anxiety-related behaviors, impaired social behaviors and impaired motor function, while they showed no significant changes in sensory functions. Similar psychiatric or psychosocial symptoms are often observed in people with ASD. Missense mutations in the CADM1 gene have been identified in ASD patients [5]. These results are consistent with an idea that deficiency in CADM1 functions is involved in pathogenesis of ASD.

The open-field and

Acknowledgment

This work was supported by KAKENHI (20590237, 20020023, 20790194, 22120512, 22659050) from MEXT and JSPS.

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1

Present address: Center for Medical Science, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi-ken 324-8501, Japan.

2

Present address: Department of Pediatrics, Shenjing Hospital of China Medical University, Heping District, Shenyang, Liaoning Province 110004, China.

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