Single-dose ethanol intoxication causes acute and lasting neuronal changes in the brain

Author:

Knabbe Johannes12ORCID,Protzmann Jil23ORCID,Schneider Niklas24ORCID,Berger Michael5,Dannehl Dominik6,Wei Shoupeng7ORCID,Strahle Christopher2,Tegtmeier Michèle5ORCID,Jaiswal Astha8,Zheng Hongwei2ORCID,Krüger Marcus9ORCID,Rohr Karl8,Spanagel Rainer10,Bilbao Ainhoa7ORCID,Engelhardt Maren611ORCID,Scholz Henrike5ORCID,Cambridge Sidney B.21213ORCID

Affiliation:

1. Department of General Psychiatry, Heidelberg University Hospital, 69120 Heidelberg, Germany

2. Functional Neuroanatomy, Heidelberg University, 69120 Heidelberg, Germany

3. Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden

4. Department of Neurology, University Hospital Zurich, 8044 Zurich, Switzerland

5. Institute for Zoology, University of Cologne, 50674 Cologne, Germany

6. Institute of Neuroanatomy, Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany

7. Behavioral Genetics Research Group, Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, 68159 Mannheim, Germany

8. Biomedical Computer Vision Group, BioQuant, IPMB, Heidelberg University, Heidelberg, 69120 Germany

9. CECAD Research Center, University of Cologne, 50931 Cologne, Germany

10. Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, 68159 Mannheim, Germany

11. Institute of Anatomy and Cell Biology, Johannes Kepler University, 4020 Linz, Austria

12. Anatomy II, Heinrich-Heine University, 40225 Düsseldorf, Germany

13. Current address: Dr. Senckenbergische Anatomie, Goethe University, 60590 Frankfurt, Germany

Abstract

Alcohol intoxication at early ages is a risk factor for the development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope–labeled mice combined with quantitative mass spectrometry to screen more than 2,000 hippocampal proteins, of which 72 changed synaptic abundance up to twofold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naïve mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference in Drosophila flies. This study introduces mitochondrial trafficking as a process implicated in reward learning and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.

Funder

Deutsche Forschungsgemeinschaft

Volkswagen Foundation

Bundesministerium für Bildung und Forschung

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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