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

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 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.

p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease

“…Further, our data indicated a possible increase of Ca 2+ -permeable GluA1 homomers (CP-AMPARs) by p85S6K. Elevated surface CP-AMPARs have been shown to facilitate LTP and improve hippocampus-dependent spatial learning [ 24 ]. The expression of GluA1 is down-regulated in the brains of AD patients and transgenic AD mice [ 59 , 60 ].…”

“…S13). Risk factors such as β-amyloid can affect the phosphorylation of GluA1 at Ser845 and surface level of GluA1, causing reduction of surface CP-AMPARs or abnormal synaptic CP-AMPAR incorporation [ 24 , 61 , 62 ]. Our study demonstrated that overexpression of p85S6K increased surface GluA1 via phosphorylation of GluA1 at Ser845 and improved learning and memory in AD mice, implicating that p85S6K may restore the CP-AMPARs in AD.…”

“…Trypsin treatment of synaptosomes was performed as previously described [ 24 ]. Briefly, the synaptosomal compartment (P2 pellet of the above fractionation) was resuspended in ice-cold sucrose buffer [320 mM sucrose and 5 mM HEPES (pH 8)].…”

Imaging of post-synaptic membrane trafficking in neuronal dendrites: progress, limitations, and new developments

“…25 Peri-PSD CCSs play a specific role in post-synaptic receptor endocytosis, 25 even if some AMPARs may internalize through clathrin independent endocytosis. [28][29][30] How does imaging of CCSs reveal the dynamics of CME? The CCSs are transient structures appearing and disappearing in living cells: this would reflect the clustering of cargo, invagination to form a vesicle, scission, clathrin uncoating, and movement away from the plasma membrane.…”

PICALM and Alzheimer’s Disease: An Update and Perspectives

“…PICALM and related ANTH-domain-containing proteins modulate the surface levels of calcium-permeable AMPA-type glutamate receptors (AMPARs) that mediate fast excitatory neurotransmission and excitotoxicity [ 61 ]. PICALM is thereby supposed to play roles in synaptic plasticity and learning by modulating both long-term potentiation (LTP) and long-term depression (LTD) [ 62 ].…”