Abstract
Chemokines are small secreted signaling proteins produced by a broad range of cells, including immune cells. Several studies have recently suggested potential roles of chemokines and their receptors in the pathophysiology of autism spectrum disorders (ASDs). SAM3 is a novel brain-specific chemokine-like molecule with an unknown physiological function. We explored the relevance of chemokines in the development of ASD in mice, with a focus on SAM3. We generated Sam3 gene knockout (KO) mice and characterized their behavioral phenotypes, with a focus on those relevant to ASD. Sam3-deficient mice displayed all three core phenotypes of ASD: impaired responses to social novelty, defects in social communication, and increased repetitive behavior. In addition, they showed increased anxiety. Interestingly, gender differences were identified for several behaviors: only male Sam3 KO mice exhibited increased anxiety and increased repetitive behaviors. Sam3 KO mice did not exhibit changes in other behaviors, including locomotor activities, fear learning and memory, and object recognition memory. These findings indicate that a deficiency of SAM3, a novel brain-specific chemokine-like molecule, may lead to the pathogenesis of ASDs and suggest the possibility that SAM3, a soluble factor, could be a novel therapeutic target for ASD treatment.
Highlights
Autism spectrum disorders (ASD) are a neurodevelopmental disorder that are mainly characterized by symptoms in social interaction, social communication and repetitive behaviors[1]
Sam[3] KO mice exhibited all three core symptoms that constitute the criteria for ASD diagnosis, which suggests that SAM3 plays a preventive role in ASD development
A transcription activator-like effector nucleases (TALEN)-mediated KO for the SAM3 gene was produced by targeting exon 4, which contains the initiation codon ATG
Summary
Autism spectrum disorders (ASD) are a neurodevelopmental disorder that are mainly characterized by symptoms in social interaction, social communication and repetitive behaviors[1]. Mice deficient in CC chemokine receptor 6 (CCR6) displayed higher locomotion, lower anxiety and a reduced preference for social novelty[14] These studies suggest that chemokines and their receptors may modulate cognition and behaviors related to ASD symptoms. Eight members of the zebrafish chemokine-like gene family were identified, which we named the Samdori (Sam) family We determined that their sequences are highly conserved with respect to the 5 sequences referred to as the FAM19A (TAFA) family sequences in the mouse and human, which have unknown functions. These genes are exclusively expressed in the central nervous system with distinct expression patterns in the mouse[15]. Sam[3] KO mice exhibited all three core symptoms that constitute the criteria for ASD diagnosis, which suggests that SAM3 plays a preventive role in ASD development
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