Membrane lipids and their metabolism have key functions in neurotransmission. Here we provide a quantitative lipid inventory of mouse and rat synaptic junctions. To this end, we developed a multiomics extraction and analysis workflow to probe the interplay of proteins and lipids in synaptic signal transduction from the same sample. Based on this workflow, we generate hypotheses about novel mechanisms underlying complex changes in synaptic connectivity elicited by environmental stimuli. As a proof of principle, this approach reveals that in mice exposed to an enriched environment, reduced endocannabinoid synthesis and signaling is linked to increased surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in a subset of Cannabinoid-receptor 1 positive synapses. This mechanism regulates synaptic strength in an input-specific manner. Thus, we establish a compartment-specific multiomics workflow that is suitable to extract information from complex lipid and protein networks involved in synaptic function and plasticity.

Emmy Noether Group 'Neuronal Protein Transport ' University Medical Center Hamburg Eppendorf Center for Molecular Neurobiology ZMNH 20251 Hamburg Germany; AG Optobiology Institute for Biology Humboldt Universität zu Berlin 10115 Berlin Germany

Institutes of Brain Science State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science Fudan University Shanghai 200032 China

Leibniz Group 'Dendritic Organelles and Synaptic Function ' University Medical Center Hamburg Eppendorf Center for Molecular Neurobiology ZMNH 20251 Hamburg Germany; RG Neuroplasticity Leibniz Institute for Neurobiology 39118 Magdeburg Germany

Leibniz Group 'Dendritic Organelles and Synaptic Function ' University Medical Center Hamburg Eppendorf Center for Molecular Neurobiology ZMNH 20251 Hamburg Germany; RG Neuroplasticity Leibniz Institute for Neurobiology 39118 Magdeburg Germany; German Center for Neurodegenerative Diseases 39120 Magdeburg Germany; Center for Behavioral Brain Sciences 30120 Magdeburg Germany

Leibniz Institut für Analytische Wissenschaften ISAS e 5 44227 Dortmund Germany

Leibniz Institut für Analytische Wissenschaften ISAS e 5 44227 Dortmund Germany; Department of Analytical Chemistry Faculty of Chemistry University of Vienna 1090 Wien Austria

Morphology and Electron Microscopy University Medical Center Hamburg Eppendorf Center for Molecular Neurobiology ZMNH 20251 Hamburg Germany

RG Neuroplasticity Leibniz Institute for Neurobiology 39118 Magdeburg Germany

University of Pardubice Department of Analytical Chemistry CZ 532 10 Pardubice Czech Republic

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