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Impairment of Social Behaviors in Arhgef10 Knockout Mice

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Impairment of Social Behaviors in Arhgef10 Knockout Mice Lu et al. Molecular Autism (2018) 9:11 https://doi.org/10.1186/s13229-018-0197-5 RESEARCH Open Access Impairment of social behaviors in Arhgef10 knockout mice Dai-Hua Lu1, Hsiao-Mei Liao2, Chia-Hsiang Chen3,4, Huang-Ju Tu1, Houng-Chi Liou1, Susan Shur-Fen Gau2* and Wen-Mei Fu1* Abstract Background: Impaired social interaction is one of the essential features of autism spectrum disorder (ASD). Our previous copy number variation (CNV) study discovered a novel deleted region associated with ASD. One of the genes included in the deleted region is ARHGEF10. A missense mutation of ARHGEF10 has been reported to be one of the contributing factors in several diseases of the central nervous system. However, the relationship between the loss of ARHGEF10 and the clinical symptoms of ASD is unclear. Methods: We generated Arhgef10 knockout mice as a model of ASD and characterized the social behavior and the biochemical changes in the brains of the knockout mice. Results: Compared with their wild-type littermates, the Arhgef10-depleted mice showed social interaction impairment, hyperactivity, and decreased depression-like and anxiety-like behavior. Behavioral measures of learning in the Morris water maze were not affected by Arhgef10 deficiency. Moreover, neurotransmitters including serotonin, norepinephrine, and dopamine were significantly increased in different brain regions of the Arhgef10 knockout mice. In addition, monoamine oxidase A (MAO-A) decreased in several brain regions. Conclusions: These results suggest that ARHGEF10 is a candidate risk gene for ASD and that the Arhgef10 knockout model could be a tool for studying the mechanisms of neurotransmission in ASD. Trial registration: Animal studies were approved by the Institutional Animal Care and Use Committee of National Taiwan University (IACUC 20150023). Registered 1 August 2015. Keywords: ARHGEF10, Autism spectrum disorder, Social deficits, Serotonin, Norepinephrine Background polygenic disease [6]. However, the genetic underpinnings Autism spectrum disorder (ASD) is a common neurode- of ASD remain unclear, which impedes understanding of velopmental disorder marked by lifetime social functional the disease pathology and the search for treatments. impairment [1, 2]. The essential features of ASD include Our previous study identified two novel chromosomal impairment in reciprocal social communication; a deficit deletions in two unrelated ASD patients [7]. One of the in communication ability; and restricted, repetitive behav- deletions, which spans 8p23.3-pter, contains three ior and interests [1]. ASD occurs at a higher incidence in genes––DLGAP2, CLN8, and ARHGEF10––that may be males than females, with a common consensus ratio of 4:1 relevant to neurological functions. The functional loss of [3]. The prevalence of ASD has been estimated at approxi- these genes might contribute to the clinical symptoms of mately 1.5% and has increased dramatically over the past ASD [8, 9]. In this study, we target the gene ARHGEF10 few decades [4, 5]. Various genetic studies have provided to further investigate the impacts of its functional loss. convincing evidence that ASD is a complex and highly ARHGEF10, as a rho guanine nucleotide exchange factor (GEF), regulates rho GTPases by catalyzing the exchange * Correspondence: [email protected]; [email protected] of G-protein-bound GDP for GTP. There are over 60 2Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan rho GEFs identified in the human genome. However, few 1Pharmacological Institute, College of Medicine, National Taiwan University, have been functionally evaluated in animal models. The Taipei, Taiwan Thr109lle mutation of the rho GEF 10 (ARHGEF10) Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lu et al. Molecular Autism (2018) 9:11 Page 2 of 14 gene was found in a family of patients with slow nerve critical role in social behavior but also participates in the conduction and thinly myelinated peripheral nerves [10]. regulation of neurotransmitters. In addition to its possible role in the myelination process, the single nucleotide polymorphism of ARH- Methods GEF10 has also been reported to be associated with Animals and experimental design schizophrenia [11]. GEFs are the main regulators that Arhgef10 knockout mice were generated by the deletion facilitate the activation of rho GTPases by converting of exon 4 and exon 5 using the Cre-loxP site-specific them from the GDP-bound state to an active GTP- knockout according to a method described previously bound state. Rho GTPases have been widely studied in [8]. The strategy for generating Arhgef10 knockout mice neuronal development and neuronal diseases [12]. Given is shown in Additional file 1: Figure S1. In brief, exons 4 the importance of rho GTPases in the nervous system, and 5 of ARHGEF10 in embryonic stem cells from the dysregulation of rho GEFs is believed to be involved in 129S1/Sv mouse strain were replaced with a construct neurodevelopmental diseases. For example, a mutation containing ARHGEF10 exons 4 and 5 interposed of ARHGEF6 has been associated with intellectual dis- between two loxP sites and a NEO cassette to produce ability [13]. These findings encouraged us to further Cre-induced homologous recombination. Arhgef10 study the possible role of ARHGEF10 in ASD. knockout mice were then backcrossed for at least ten To explore the role of ARHGEF10 in ASD and to generations with C57BL/6J mice. The Arhgef10 knockout further understand the impacts of ARHGEF10 deletion mice used in this study were produced by heterozygous on the molecular mechanisms of neurological function, breeding pairs in a trio breeding format. All mice were we generated an Arhgef10 knockout mouse model by de- kept under standard temperature, humidity, and timed leting exons 4 and 5 of the mouse Arhgef10 gene. The lighting conditions and provided with mouse chow and mice without the Arhgef10 gene have normal fertility water ad libitum. Arhgef10 knockout mice and their and body weight gain. The Arhgef10 knockout mice were control littermates were housed in groups (3–5 mice then subjected to tests measuring their startle responses, per cage). motor behavior, spatial learning, and social behavior. Be- Behavioral tests were conducted during the light cycle havioral changes may reflect a disturbance of neuro- (07:00–19:00) in a testing room next to the mouse hous- transmission. Previous studies have shown that the ing room. Eight- to twelve-week-old male Arhgef10 KO dysregulation of biosynthesis, transportation, and deg- mice and their WT littermates were used in this study. radation of neurotransmitters could be associated with All behavioral tests were carried out with male mice. ASD [14]. In addition, genetic association studies have Animals in the same littermates were used in the same identified some genes that encode the transporters or behavioral test, except for the plus maze, open field, and degradation enzymes of neurotransmitters as contribut- water maze tests. In these three tests, the intervals ing to the risk of ASD [15]. For instance, monoamine between tests were approximately 7 days each. The open oxidase A (MAO-A), an enzyme that is important for field test was conducted first, followed by the plus maze the metabolism of serotonin and norepinephrine, is as- and then the water maze. Mice were transported to the sociated with ASD in a population-based study [15]. An- testing room and habituated for 30 min before behav- other population-based association study also indicates ioral testing. All animal experiments were approved by that changes in monoamine oxidase B (MAO-B) activity the Ethical Committee for the Animal Research of increase ASD risk in males [16]. Based on those findings, National Taiwan University. we evaluated the levels of monoamines in Arhgef10 knockout mice to understand the possible roles of Arh- Sample preparation gef10 in the serotonergic system. Mice were anesthetized with isoflurane and then decapi- In this study, we found that Arhgef10 knockout mice tated. For Nissl staining, the brains of 10-week-old mice exhibited impaired social interaction and social recogni- were removed after saline perfusion and post-fixed with tion, representing the key characteristics of ASD. In 4% paraformaldehyde (PFA) overnight. Tissue samples addition, Arhgef10 knockout mice also displayed reduced for Western blots and high-performance liquid chroma- anxiety-like and depression-like behaviors and increased tography (HPLC) were prepared by dissecting four parts locomotor activity. Additionally, serotonin, norepineph- from the fresh brains of 10- to 12-week-old mice: frontal rine, and dopamine were elevated in the frontal cortex, cortex, striatum, hippocampus, and amygdala. These tis- hippocampus, and amygdala in Arhgef10 knockout mice. sues were then weighed and homogenized. Moreover, MAO-A, a molecule that regulates the levels
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