Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders

Sep 30, 2026

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Autism spectrum disorder (ASD) includes diverse neurodevelopmental conditions in which behavioral symptoms are central to diagnosis. 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.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages42

Reading Time1 h 46 min

AccessFree to download

Summary

In brief

Author contributions

Introduction

Background on ASD and striatal dopamine

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Cell Rep. Author manuscript; available in PMC 2026 January 07. | | --- | --- | Published in final edited form as: Cell Rep. 2024 December 24; 43(12): 114997. doi:10.1016/j.celrep.2024.114997 . Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders Josep 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,* 1 Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden 2 Department of Psychiatry, Columbia University Irving Medical Center, New York, NY 10032, USA 3 New York State Psychiatric Institute, New York, NY 10032, USA 4 Pronexus Analytical AB, 16733 Stockholm-Bromma, Sweden 5 Department of Neurology, University of California San Francisco (UCSF), San Francisco, CA 94143, USA 6Lead contact SUMMARY Autism 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. In brief This is an open access article under the CC BY license ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). *Correspondence: [anders.borgkvist@ki.se](anders.borgkvist@ki.se) (A.B.), [emanuela.santini@ki.se](emanuela.santini@ki.se) (E. S.) . AUTHOR CONTRIBUTIONS Conceptualization, 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., A.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 E. S. DECLARATION OF INTERESTS The authors declare no competing interests. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Carbonell-Roig et al. Page 2 Basal ganglia dysfunction potentially causes behavioral alterations in ASD. Carbonell-Roig et al. show 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. Graphical Abstract INTRODUCTION Autism 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

FAQs

What condition and key behavioral aspect does the study focus on?

The study focuses on autism spectrum disorder (ASD), emphasizing core behavioral symptoms and their relationship to brain neurotransmission changes.

How does the eIF4E Tg mouse model affect dopamine-related outcomes?

Increased eIF4E expression leads to behavioral inflexibility and impaired dopamine release in the striatum.

What cellular mechanism explains the disrupted ACh–DA link in the model?

The loss of normal dopamine neurotransmission is attributed to defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons.

Sep 30, 2026

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