Impairment of social and emotional behaviors in Cadm1-knockout mice
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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2020, Biological PsychiatryCitation Excerpt :It is involved in homophilic as well as heterophilic binding with other members of the SynCAM family (specifically with SynCAM2), and also interacts with CASK (calmodulin-dependent serine protein kinase) and syntenin (82,83). Knockout of the Cadm1 gene led to a decrease in social affiliation (87). NEGR1 (neural growth regulator 1) (also known as Kilon/IGLON4) is a glycosylphosphatidylinositol-linked member of the IgLON family, a subfamily of the IgSF, and is involved in the regulation of synapses, largely active in axons, growth cones, and presynaptic terminals early in development and in spines later in development (88).
Identification of rare variants in CADM1 in patients with anorexia nervosa
2020, Psychiatry ResearchCitation Excerpt :In 2005, CADM1 was shown to be early expressed during brain development (since E9.5 in mice), particularly in axons suggesting a role in cortical migration and axonal growth (Fujita et al., 2005). It is also expressed in excitatory and inhibitory neurons suggesting a role in synaptogenesis (Thomas et al., 2008) and more particularly at the level of growth cones (Robbins et al., 2010; Takayanagi et al., 2010; Krzisch et al., 2017), which negatively regulates the morphological complexity. The biochemical mechanism is still unknown but could correspond to activation of the PI3K pathway by formation of a MAGuK-MPP3-Dlg complex through a trans-homophilic interaction (Murakami et al., 2014).
SynCAMs – From axon guidance to neurodevelopmental disorders
2017, Molecular and Cellular NeuroscienceCitation Excerpt :These findings were in line with observations in animal models, despite the fact that animal models only reflect isolated traits of these complex human disorders. SynCAM1 knockout mice exhibit deficits in social and emotional behavior, as well as impaired ultrasonic vocalization (Takayanagi et al., 2010; Fujita et al., 2012). Transgenic and knockout mice showed altered spatial learning, as mice overexpressing SynCAM1 in excitatory synapses performed worse, whereas SynCAM1 knockout mice performed better (Robbins et al., 2010).
Autism and cerebellar dysfunction: Evidence from animal models
2016, Seminars in Fetal and Neonatal MedicineCitation Excerpt :Cadm1 shows high expression in Purkinje cell dendrites while Cadm1 mutant mice display a small cerebellum. These mutant mice also have social impairment, abnormal vocalizations, anxiety, and abnormal motor function [48], consistent with findings seen in ASD. Retinoic acid receptor-related orphan receptor alpha (Rorα) is a transcription factor that is also an ASD candidate gene [49].
Mouse Behavior and Models for Autism Spectrum Disorders
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability
- 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.