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Altered dopamine neurotransmission in the striatum is implicated in ASD behavioral features. This study investigates dopamine release in an ASD mouse model with elevated eIF4E, a regulator of cap-dependent translation, using genetics, behavior, synaptic physiology, and imaging. Results show eIF4E-driven behavioral inflexibility and impaired striatal dopamine release due to defective nicotinic receptor signaling that controls calcium dynamics in dopaminergic axons.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/dysregulated-acetylcholine-mediated-dopamine-neurotransmission-in-the-eif4e-tg-mouse-model-of-autism-spectrum-disorders/455617/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/dysregulated-acetylcholine-mediated-dopamine-neurotransmission-in-the-eif4e-tg-mouse-model-of-autism-spectrum-disorders/455617.png","ImageObject",300,407,{"name":92,"@type":93},"Asher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-08","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What condition and key behavioral aspect does the study focus on?","Question",{"text":112,"@type":113},"The study focuses on autism spectrum disorder (ASD), emphasizing core behavioral symptoms and their relationship to brain neurotransmission changes.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does the eIF4E Tg mouse model affect dopamine-related outcomes?",{"text":117,"@type":113},"Increased eIF4E expression leads to behavioral inflexibility and impaired dopamine release in the striatum.",{"name":119,"@type":110,"acceptedAnswer":120},"What cellular mechanism explains the disrupted ACh–DA link in the model?",{"text":121,"@type":113},"The loss of normal dopamine neurotransmission is attributed to defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455617,1790791231,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687197207639,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Cell Rep. Author manuscript; available in PMC 2026 January 07. |\n| --- | --- |\n\nPublished in final edited form as:  \nCell Rep. 2024 December 24; 43(12): 114997. doi:10.1016/j.celrep.2024.114997 .  \nDysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders  \nJosep Carbonell-Roig 1 , Alina Aaltonen 1 , Karin Wilson 1 , Maya Molinari 1 , Veronica Cartocci 1 , Avery McGuirt2,3 , Eugene Mosharov2,3 , Jan Kehr4 , Ori J. Lieberman2,3,5 , David Sulzer2,3 , Anders Borgkvist 1,* , Emanuela Santini 1,6,*  \n1 Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden  \n2 Department of Psychiatry, Columbia University Irving Medical Center, New York, NY 10032, USA  \n3 New York State Psychiatric Institute, New York, NY 10032, USA  \n4 Pronexus Analytical AB, 16733 Stockholm-Bromma, Sweden  \n5 Department of Neurology, University of California San Francisco (UCSF), San Francisco, CA 94143, USA  \n6Lead contact  \nSUMMARY  \nAutism spectrum disorder (ASD) consists of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine (DA) neurotransmission in thestriatum has been suggested to contribute to the behavioral features of ASD. Here, we examine DAneurotransmission in a mouse model of ASD characterized by elevated expression of eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal DA release. The loss of normal DA neurotransmission is due to a defect in nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions by revealing the intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility.  \nIn brief  \nThis is an open access article under the CC BY license ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)).  \n*Correspondence: [anders.borgkvist@ki.se](anders.borgkvist@ki.se) (A.B.), [emanuela.santini@ki.se](emanuela.santini@ki.se) (E. S.) .  \nAUTHOR CONTRIBUTIONS  \nConceptualization, O.J.L., A.B., and E.S.; methodology, A.B. and E.S.; validation, A.B. and E.S.; formal analysis, J.C.-R., A.A.,  \nA.B., and E.S.; investigation, J.C.-R., A.A., A.M., E.M., J.K., O.J.L., M.M., K.W., V.C., A.B., and E.S.; resources, A.B. and E.S.; writing – original draft, A.B. and E.S.; writing – review & editing, J.C.R., A.A., M.M., V.C., E.M., J.K., O.J.L., D.S., A.B., and E.S.; visualization, J.C.R., A.B., and E.S.; supervision, A.B. and E.S.; project administration, A.B. and E.S.; funding acquisition, A.B. and  \nE. S.  \nDECLARATION OF INTERESTS  \nThe authors declare no competing interests.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nCarbonell-Roig et al. Page 2  \nBasal ganglia dysfunction potentially causes behavioral alterations in ASD. Carbonell-Roig et al.  \nshow that the eIF4E Tg mouse model of ASD exhibits behavioral inflexibility and impaired striatal dopamine release, linked to disrupted β2-nAChR function on DA axons. Thus, altered striatal ACh-DA interactions constitute a cellular basis for ASD-like behavioral inflexibility.  \nGraphical Abstract  \nINTRODUCTION  \nAutism spectrum disorder (ASD) encompasses a diverse set of polygenic neurodevelopmental conditions defined by core behavioral symptoms, such as repetitive, stereotyped behaviors and abnormal social interactions.1 The behavioral manifestations within ASD are heterogeneous and are often complicated by comorbidities. Thus, the clinical diagnosis of ASD is challenging, s","cbCailOcZfFfuaML","https://ap.wps.com/l/cbCailOcZfFfuaML","pdf",2026812,42,"English","# Summary\n## In brief\n## Author contributions\n## Introduction\n## Background on ASD and striatal dopamine","[{\"question\":\"What condition and key behavioral aspect does the study focus on?\",\"answer\":\"The study focuses on autism spectrum disorder (ASD), emphasizing core behavioral symptoms and their relationship to brain neurotransmission changes.\"},{\"question\":\"How does the eIF4E Tg mouse model affect dopamine-related outcomes?\",\"answer\":\"Increased eIF4E expression leads to behavioral inflexibility and impaired dopamine release in the striatum.\"},{\"question\":\"What cellular mechanism explains the disrupted ACh–DA link in the model?\",\"answer\":\"The loss of normal dopamine neurotransmission is attributed to defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons.\"}]","Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders | PDF",1790743645,106]