Selective endocytosis of Ca²⁺-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
Sci. Adv.. 2022-05-27; 8(21):
DOI: 10.1126/sciadv.abl5032


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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 Ca2+ -permeable (CP) versus heteromeric Ca2+ -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.

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