Selective endocytosis of Ca 2+ -permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity

Domenico Azarnia Tehran; Gaga Kochlamazashvili; Niccolò P Pampaloni; Silvia Sposini; Jasmeet Kaur Shergill; Martin Lehmann; Natalya Pashkova; Claudia Schmidt; Delia Löwe; Hanna Napieczynska; Arnd Heuser; Andrew J R Plested; David Perrais; Robert C Piper; Volker Haucke; Tanja Maritzen

doi:10.1126/sciadv.abl5032

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Selective endocytosis of Ca 2+ -permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity

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Selective endocytosis of Ca 2+ -permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity

Domenico Azarnia Tehran, Gaga Kochlamazashvili, Niccolò P Pampaloni, Silvia Sposini, Jasmeet Kaur Shergill, Martin Lehmann, Natalya Pashkova, Claudia Schmidt, Delia Löwe, Hanna Napieczynska, …

Science advances, Vol.8(21), p.eabl5032

05/27/2022

DOI: 10.1126/sciadv.abl5032

PMCID: PMC9132451

PMID: 35613266

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Abstract

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission, and the plastic modulation of their surface levels determines synaptic strength. AMPARs of different subunit compositions fulfill distinct roles in synaptic long-term potentiation (LTP) and depression (LTD) to enable learning. Largely unknown endocytic mechanisms mediate the subunit-selective regulation of the surface levels of GluA1-homomeric Ca -permeable (CP) versus heteromeric Ca -impermeable (CI) AMPARs. Here, we report that the Alzheimer's disease risk factor CALM controls the surface levels of CP-AMPARs and thereby reciprocally regulates LTP and LTD in vivo to modulate learning. We show that CALM selectively facilitates the endocytosis of ubiquitinated CP-AMPARs via a mechanism that depends on ubiquitin recognition by its ANTH domain but is independent of clathrin. Our data identify CALM and related ANTH domain-containing proteins as the core endocytic machinery that determines the surface levels of CP-AMPARs to bidirectionally control synaptic plasticity and modulate learning in the mammalian brain.

Alzheimer Disease - etiology

Animals

Endocytosis

Mammals - metabolism

Neuronal Plasticity - physiology

Receptors, AMPA - metabolism

Risk Factors

Details

Title: Subtitle: Selective endocytosis of Ca 2+ -permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity
Creators: Domenico Azarnia Tehran - Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Roessle-Straße 10, 13125 Berlin, Germany
Gaga Kochlamazashvili - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Niccolò P Pampaloni - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Silvia Sposini - Interdisciplinary Institute for NeuroScience
Jasmeet Kaur Shergill - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Martin Lehmann - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Natalya Pashkova - Roy J. and Lucille A. Carver College of Medicine
Claudia Schmidt - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Delia Löwe - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Hanna Napieczynska - Max Delbrück Center for Molecular Medicine
Arnd Heuser - Max Delbrück Center for Molecular Medicine
Andrew J R Plested - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
David Perrais - Interdisciplinary Institute for NeuroScience
Robert C Piper - Roy J. and Lucille A. Carver College of Medicine
Volker Haucke - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Tanja Maritzen - Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Resource Type: Journal article
Publication Details: Science advances, Vol.8(21), p.eabl5032
DOI: 10.1126/sciadv.abl5032
PMID: 35613266
PMCID: PMC9132451
NLM abbreviation: Sci Adv
ISSN: 2375-2548
eISSN: 2375-2548
Language: English
Date published: 05/27/2022
Academic Unit: Molecular Physiology and Biophysics; Medicine Administration; Internal Medicine
Record Identifier: 9984297510702771

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