AMPA Receptors in Synaptic Plasticity, Memory Function, and Brain Diseases

Abstract

Tetrameric AMPA-type ionotropic glutamate receptors are primary transducers of fast excitatory synaptic transmission in the central nervous system, and their properties and abundance at the synaptic surface are crucial determinants of synaptic efficacy in neuronal communication across the brain. The induction of long-term potentiation (LTP) leads to the insertion of GluA1-containing AMPA receptors at the synaptic surface, whereas during long-term depression (LTD), these receptors are internalized into the cytoplasm of the spine. Disruptions in the trafficking of AMPA receptors to and from the synaptic surface attenuate both forms of synaptic plasticity. Homeostatic scaling up and scaling down, which are additional types of plasticity similar to LTP and LTD, are also regulated by the insertion and removal of GluA1-containing AMPA receptors from the synaptic surface. The trafficking of AMPA receptors is an intricate process assisted by various proteins. Furthermore, AMPA receptors are critical for the formation and consolidation of various types of memory, and alterations in their function are intimately associated with cognitive dysfunction in aging and several neurological and psychiatric diseases. In this review, we will provide an overview of the current understanding of how AMPA receptors regulate various forms of synaptic plasticity, their contribution to memory functions, and their role in aging and brain diseases.

Keywords: AMPA receptors; Aging and neurological diseases; Homeostatic plasticity; LTP and LTD; Memory; Trafficking.

Fig. 1

Glutamate receptors at the synaptic surface. A stimulus-mediated glutamate release activates ionotropic AMPA and NMDA receptors, as well as G-protein-coupled mGluRs. Activation of AMPA and NMDA receptors leads to the influx of Na⁺ and Ca²⁺, respectively. The influx of Ca²⁺ activates CaMKII, which is essential for the phosphorylation of AMPA receptors and the induction of synaptic potentiation. In contrast, activation of mGluRs triggers a signaling cascade through second messengers

Fig. 2

AMPA receptors in LTP and LTD. During LTP (left), GluA1-containing AMPA receptors are inserted into the synaptic surface to maintain synaptic strength, whereas during LTD (right), GluA1-containing AMPA receptors are internalized, leading to synaptic depression. CaN calcineurin; PP1 protein phosphatase 1

Fig. 3

AMPA receptors trafficking during LTP. AMPA receptor subunits are synthesized and assembled in the endoplasmic reticulum, and are then exported to the cytosol, where SAP97 binds to the C-terminus of the GluA1 subunit of AMPA receptors and interacts with the actin-associated protein 4.1N to mediate perisynaptic surface membrane insertion of GluA1-containing AMPA receptors. Once at the perisynaptic membrane, these AMPA receptors laterally diffuse through the surface membrane to reach the postsynaptic density area, where they bind to phosphorylated TARP (pTARP) associated with PSD-95. The binding of GluA1-containing AMPA receptors to the pTARP-(PSD-95) protein complex traps them at the synaptic surface. At the same time, GluA2-containing AMPA receptors are retained at the perisynaptic membrane. NMDA receptor-mediated Ca²⁺ influx and activation of CaMKII induce phosphorylation at the S831 site of the GluA1 subunit, promoting LTP and the maintenance of synaptic strength. cAMP cyclic AMP; Syt1 synaptotagmin 1; Syb2 synaptobrevin 2; PICK protein interacting with C Kinase 1; DAG diacylglycerol; TARP transmembrane AMPA receptor regulatory protein

Fig. 4

AMPA receptors trafficking during LTD. Phosphatase PP1-mediated dephosphorylation of pTARP disrupts its interaction with PSD-95, freeing the trapped GluA1-containing AMPA receptors. The liberated GluA1 subunits of AMPA receptors are then dephosphorylated at the S845 site and the dephosphorylated TARP binds with Arc, forming the Arc-TARP-AMPA receptor protein complex. This protein complex diffuses through the surface membrane toward the endocytic zone, where Arc and the GluA2 subunit of GluA1-containing AMPA receptors, via PICK1, interact with the AP2 complex for clathrin-mediated endocytosis (inset). TARP transmembrane AMPA receptor regulatory protein; PP1 protein phosphatase 1; CaN calcineurin; NSF N-ethylmaleimide-sensitive fusion protein; GRIP glutamate receptor interacting protein 1; AP2 assembly polypeptide 2 complex; PICK1 protein interacting with C Kinase 1; Arc Activity-regulated cytoskeleton-associated protein

Fig. 5

AMPA receptors in Hebbian and homeostatic plasticity. In Hebbian plasticity, synaptic incorporation and CaMKII-mediated phosphorylation at the S831 site of GluA1-containing AMPA receptors lead to synaptic strengthening (LTP, top left), while dephosphorylation at the S845 site and removal of these receptors from the synaptic surface cause synaptic weakening (LTD, bottom left). In contrast, in homeostatic plasticity, phosphorylation of the S845 site by PKA, associated with AKAP5, results in receptor accumulation at the synaptic surface (scaling-up, top right), whereas reduced PKA activity and S845 dephosphorylation by calcineurin (CaN) decrease receptor presence at the synaptic surface (scaling-down, bottom right). CaN calcineurin; TARP transmembrane AMPA receptor regulatory protein; GRIP glutamate receptor interacting protein 1; Arc activity-regulated cytoskeleton-associated protein; cAMP cyclic AMP; PP1 protein phosphatase 1

Fig.6

AMPA receptor trafficking in aging and AD. During aging, LTP becomes less robust, an effect thought to be associated with hypofunction in AMPA receptors. There are two views on how this occurs: one suggests an overall decrease in receptor signaling due to a reduced abundance of AMPA receptors at the synaptic surface, while the other proposes that there is reduced conductance because AMPA receptors at the synaptic surface are modified, altering their function. In Alzheimer’s disease, however, Aβ interferes with CaMKII activity, and the lack of CaMKII-mediated phosphorylation of TARP and the GluA1 subunit disrupts the retention of GluA1-containing AMPA receptors at the synaptic surface, leading to an impairment in LTP. ERK extracellular signal-regulated kinase; CREB cAMP response element-binding protein; JNK c-Jun N-terminal kinase; P38 MAPK p38 mitogen-activated protein kinase; NO nitric oxide; GSK3b glycogen synthase kinase 3b; pCREB phosphorylated cAMP response element-binding protein