Selective endocytosis of Ca(2+)-permeable AMPARs by the Alzheimer's disease risk factor CALM bidirectionally controls synaptic plasticity
Autor/innen
- D. Azarnia Tehran
- G. Kochlamazashvili
- N. P. Pampaloni
- S. Sposini
- J.K. Shergill
- M. Lehmann
- N. Pashkova
- C. Schmidt
- D. Löwe
- H. Napieczynska
- A. Heuser
- A.J.R. Plested
- D. Perrais
- R.C. Piper
- V. Haucke
- T. Maritzen
Journal
- Science Advances
Quellenangabe
- Sci Adv 8 (21): eabl5032
Zusammenfassung
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(2+)-permeable (CP) versus heteromeric Ca(2+)-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.