AMPARs and synaptic plasticity: the last 25 years

Abstract

The study of synaptic plasticity and specifically LTP and LTD is one of the most active areas of research in neuroscience. In the last 25 years we have come a long way in our understanding of the mechanisms underlying synaptic plasticity. In 1988, AMPA and NMDA receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. It is now clear that the modulation of the AMPA receptor function and membrane trafficking is critical for many forms of synaptic plasticity and a large number of proteins have been identified that regulate this complex process. Here we review the progress over the last two and a half decades and discuss the future challenges in the field.

Figure 1. Model Published in 1988 for the Mechanism of Induction of LTP in the CA1 Region of the Hippocampus

(A) The events occurring during low-frequency synaptic transmission. Glutamate is released from the presynaptic terminal and acts on both the NMDA and the Q/K type of receptors (now called AMPA Receptors). Na⁺ and K⁺ flow through the Q/K receptor channel, but not through the NMDA receptor channel, due to Mg⁺² block of this channel. (B) The events occurring when the postsynaptic membrane is depolarized, as would occur during a high-frequency tetanus. The depolarization relieves the Mg⁺² block of the NMDA channel, allowing Na⁺, K⁺, and most importantly Ca⁺² to flow through the channel. The rise in Ca⁺² in the dendritic spines is proposed to provide a trigger for subsequent events leading to LTP. Depolarization would also open voltage-dependent Ca⁺² channels on the dendritic shafts, but this source of Ca⁺² does not have access to the spine. It is important to note that this model includes only events involved in the induction of LTP and not in its maintenance (taken from Nicoll et al., 1988).

Figure 2. Dynamic AMPAR Trafficking during Synaptic Plasticity

AMPARs are now known to rapidly traffic between membrane compartments and to be highly mobile within the plasma membrane. Receptors rapidly move laterally in the extrasynaptic plasma membrane and can enter and exit synapses where they interact with scaffold proteins within the PSD to immobilize them and concentrate them at the synaptic plasma membrane. The receptors can be endocytosed and then move through endosomal compartments to be sorted for degradation or for recycling back to the plasma membrane. This trafficking is highly regulated during LTP and LTD resulting in increases or decreases in the steady state level of receptors at the synapse. During LTP, receptors from nonsynaptic pools, either from the dendritic shaft plasma membrane or from intracellular pools, are recruited to synapses to potentiate synaptic transmission. In contrast, during LTD, receptors diffuse from the synapse and are then endocytosed and degraded resulting in decreases in synaptic strength.

Figure 3. Scaffolding and Trafficking Proteins Involved in AMPAR Membrane Trafficking and Synaptic Plasticity

Over the last 25 years a molecular machine involved in the structure and function of the excitatory synapse and the regulation of AMPAR membrane trafficking has been revealed. Dozens of proteins have been identified including signaling proteins such as protein kinases (PKA, CaMKII, PKC) and phosphatases (PP2B, PP1) that regulate receptor trafficking as well as proteins that directly or indirectly interact with receptors to immobilize them within the PSD. Central to this PSD structural complex are the MAGUKs, PSD-95, PSD-93, SAP97, and SAP102, which interact with many other proteins to modulate the structure and function of the synapse. Additional proteins, such as NSF, GRIP1/2, and PICK, can couple receptors to the endocytic or exocytic machinery to regulate exocytosis or endocytosis or help escort them through endosomal pathways. Recently, several transynaptic proteins such as neuroligins, neurexins, and the LRRTMs have been linked not only to synapse formation but also to AMPAR trafficking and synaptic plasticity. For reviews, see Anggono and Huganir (2012), Sheng and Sala (2001), Shepherd and Huganir (2007), Xu (2011), and Zheng et al. (2011).

Figure 4. Proposed Working Models for LTP

PSD-centric capture model. In this model CaMKII and downstream signaling cascades act on the PSD to create slots to capture receptors and increase synaptic strength. The identity of these slots is still not known but may involve the MAGUK proteins or other PSD structural proteins. The slots must be rather promiscuous because they are unable to distinguish between AMPARs and kainate receptors. Receptor-centric capture model. In this model the slots are present at the PSD but are unable to accommodate and trap the receptors. CaMKII and downstream signaling cascades target the receptors and phosphorylates the receptor complex such that the receptors are now captured by the PSD. In this scenario the C-terminal domains would play an important modulatory role but are not essential. Receptor insertion model. In this model activation of CaMKII acts on membrane trafficking machinery and drives the exocytosis of glutamate receptor-containing vesicles onto the surface, increasing the level of receptors at the synapse and synaptic strength.