Copper-deficiency is associated with impairments in social behavior and oligodendrocyte development via mTOR signaling pathway

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by impaired social communication and restricted repetitive behaviors, however the biological mechanisms remain unclear. Although trace elements play essential roles in the living body, it is unclear how alterations of trace elements in ASD are involved in pathogenesis. Here we analyzed the plasma metallome and identified the alterations of 11 elements in individuals with ASD. The copper decrease was negatively correlated with ASD symptom scores. A copper-deficient mouse model reflecting the condition showed ASD-like behaviors and impaired oligodendrocyte development. In copper-deficient mice, mechanistic target of rapamycin (mTOR) signaling was reduced, and its activation by agonist improved social impairment and oligodendrocyte developmental defects. Supporting these results, white matter volumes were negatively correlated with social symptoms in individuals with ASD. Our results demonstrate that copper-deficiency contributes to ASD by causing oligodendrocytes impairment via mTOR signaling. Our findings indicate that the effects of copper-deficiency and mTOR imbalance are relevant to the pathogenesis of ASD and are potential therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was founded by The Japan Agency for Medical Research and Development (AMED) Translational Research Grant Seeds A140 (NU, SS), AMED-CREST 22gm1510009h0001 (MM), AMED-PRIM 21wm04250XXs0101 (MM), AMED 21uk1024002s0201 (MM), 20gm6310015h0001 (MM), The Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (B) 23H02837 (NU), 19H03581 (HM), 20H03604 (MM), JSPS Grant-in-Aid for Scientific Research (C) 20K06872 (NU), JSPS Grant-in-Aid for Early-Career Scientists 23K14443 (MD), JSPS Grant-in-Aid for Challenging Research (Exploratory) 19K21754 (HM), Uehara Memorial Foundation (NU), Takeda Science Foundation (NU), Naito Foundation (NU) Mochida Memorial Foundation for Medical and Pharmaceutical Research (NU), Inamori Foundation (NU), SENSHIN Medical Research Foundation (NU), Osaka Medical Research Foundation for Intractable Diseases (NU, MD), MEI Grant supported by Osaka University (NU), and Osaka University Medical Doctor Scientist Training Program (NN). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All procedures were approved by the Ethics Committee of Osaka University (#19394), University of Fukui (#20200112), and Nara Medical University (#1319), and were conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare of Japan. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the findings of this study are available from the corresponding author upon reasonable request.