Impairment of social and emotional behaviors in Cadm1-knockout mice Yuki Takayanagi a , Eriko Fujita b,c,1 , Zhiling Yu c,2 , Takanori Yamagata c , Mariko Y. Momoi c , Takashi Momoi b,1 , Tatsushi Onaka a, * a Department of Physiology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan b Division of Development and Differentiation, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan c Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan article info Article history: Received 23 April 2010 Available online 5 May 2010 Keywords: Cell adhesion molecule 1 (CADM1) Social behavior Anxiety-related behavior Motor function Autism 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 perfor- mances 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. Ó 2010 Elsevier Inc. All rights reserved. 1. Introduction CADM1 (previously known as TSLC1, IGSF4, SgIGSF, SynCAM1, Necl2, RA175), a member of the immunoglobulin (Ig) superfamily, is a synaptic cell adhesion molecule [1–4]. CADM1 contains three extracellular Ig-like domains followed by a single transmembrane region and a short cytosolic sequence that interacts with PDZ (post- synaptic density-95 (PSD-95)/Discs large/zona occludens-1) do- mains of synaptic scaffolding molecules [1]. CADM1 is required for synapse formation and maturation of presynaptic terminals [1–4]. 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 mem- bers [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 sur- face 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. 2. Materials and methods 2.1. 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 per- formed 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 institutional committee and were in accord with Japanese legislation concerning animal experiments. 2.2. Behavioral studies 2.2.1. Open-field test To assess spontaneous locomotor activity and anxiety-related behavior, 10–15-week-old mice were placed in a corner of an 0006-291X/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2010.04.165 Abbreviations: CADM1, cell adhesion molecule 1; ASD, autism spectrum disorder; KO, knockout; Ig, immunoglobulin; ANOVA, analysis of variance; ER stress, endoplasmic reticulum stress. * Corresponding author. Address: Division of Brain and Neurophysiology, Depart- ment of Physiology, Jichi Medical University, Shimotsuke-shi, Tochigi-ken 329- 0498, Japan. Fax: +81 285 44 8147. E-mail address: tonaka@jichi.ac.jp (T. Onaka). 1 Present address: Center for Medical Science, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi 324-8501, Japan. 2 Present address: Department of Pediatrics, Shenjing Hospital of China Medical University, Heping District, Shenyang, Liaoning Province 110004, China. Biochemical and Biophysical Research Communications 396 (2010) 703–708 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc