AMPA receptor nanoscale dynamic organization and synaptic plasticities
Introduction
Since the emergence of the postulate that activity-dependent modulation of excitatory synaptic transmission could be a substrate of learning and memory [1], intense research has focused on understanding the molecular mechanisms through which neuronal activity could rapidly and endurably modify synaptic properties. Importantly, for any set of mechanisms to account for activity-driven synaptic plasticity, it has to have a fast (seconds) onset and sustain long-term changes. This is derived from experimental observations that robust changes in synaptic transmission can be induced by short tetanic activity and are maintained over hours and even days. Fast excitatory neurotransmission is mediated by glutamate, mostly occurs at small protrusions along dendrites – synaptic spines – and is almost exclusively mediated by AMPA subtype of ionotropic glutamate receptors (AMPAR). A major step forward in our understanding of the mechanisms of synaptic plasticity was achieved at the turn of the XXIst century, when studies from a number of laboratories proposed that rapid activity-driven changes in the number of AMPAR facing glutamate release sites could be the main substrate for modulations of synaptic efficacy [2,3]. The correlate hypothesis that AMPAR could enter and leave synapses within minutes to seconds came at a noticeable variance from the former view that synaptic receptor numbers were quite stable over time and that only changes in transmitter release or post-translational modifications of existing receptors could rapidly affect the efficacy of synaptic transmission [4].
Our current understanding for AMPAR dynamics is that they are trafficked through multiple pathways, including diffusion in the ER, directed intracellular vesicular transport on microtubules, exocytosis to the cell surface, endocytosis from the cell surface and random Brownian diffusion at the neuronal surface (in Ref. [4]) (Figure 1a). Each of these pathways can be modulated by neuronal activity, and thus likely contributes to regulate AMPAR numbers at synapses during activity dependent synaptic plasticities.
Setting AMPAR number at synapses results from a dynamic interplay between these trafficking pathways, the regulation of the total amount of AMPAR through biosynthesis and their postsynaptic stabilization. Surprisingly, despite major progress, the exact mechanisms through which AMPAR are reversibly stabilized at synapses and how this is controlled during various synaptic plasticities still remains elusive. This originates in part from the plethora of identified molecular AMPAR interactors. First and foremost, AMPAR form a complex with a variety of auxiliary subunits [5•] who all seem to regulate AMPAR function. In turn, each of the AMPAR pore-forming and auxiliary subunits can bind a variety of intracellular scaffold elements, and possibly extracellular matrix and adhesion proteins (e.g. and in Refs. [6,7]). Most of these interactions are regulated by neuronal activity and are thus candidates for reversible synaptic stabilization of AMPAR. While modulation of both AMPAR stabilization and trafficking processes seem to be involved in synaptic plasticity events, the respective exact contribution of each modality is still relatively mysterious.
In addition to the mere number of synaptic AMPAR, their precise localization with respect to glutamate release sites is a determinant factor of the efficacy of synaptic transmission. Indeed, AMPAR have a low affinity for glutamate and are thus only efficiently activated when located in the post-synaptic membrane within less than ∼100 nm of pre-synaptic glutamate release sites. In addition, sites of AMPAR trafficking between the cell surface and intracellular compartments are distributed all along the neuronal membrane and are not particularly localized at synapses. Hence, AMPAR surface diffusion is likely to play a key role both as a shuttling system between synaptic sites and extrasynaptic sites of recycling, and as a mechanism for rapid entry and exit of receptors from an area where they can be activated by transmitter release. We will review here the recent studies that have facilitated our understanding of the relationship between AMPAR dynamics, their nanoscale organization and synaptic plasticities, and highlight the outstanding questions.
Section snippets
The standard view of AMPA receptor dynamics in synaptic long-term plasticity and outstanding questions
Activity dependent long-term post-synaptic plasticity of excitatory synapses is thought to be mainly due to a change in the total synaptic AMPAR content (in Ref. [4]). Specific patterns of input activity trigger a chronological series of events, including activation of calcium permeable channels (such as NMDA and calcium permeable AMPA type glutamate receptors or voltage dependent calcium channels) leading to calcium influx that trigger a variety of signaling pathways, including first and
AMPAR nano-organization and synaptic function
The central role of AMPAR nanoscale organization in setting synaptic strength originates from the low affinity of AMPAR for glutamate and the correlate that all synaptic AMPAR are not activated by a single vesicle release. Already in the 2000’s, it was established that only ∼25% of synaptic AMPAR are activated by a single glutamate release event [13]. This observation was confirmed by the difference between the quantity of AMPAR per spine estimated with biochemistry [7], electron microscopy [26
Rapid AMPAR diffusion in short-term plasticity
The contributors to somatically recorded synaptic current amplitudes, proposed more than 5 decades ago, can be summarized by I = NPQ. With I being the current intensity recorded at the soma, N the number of synapses, P the pre-synaptic release probability (Pr) and Q the quantal response to a vesicle release, merging glutamate content, receptor numbers and activation probabilities. The time dependent evolution of synaptic responses during high frequency stimulation, HF-STP, can be either a
Outlook
Reconciling AMPAR dynamics, the robustness of synaptic transmission and its plasticity over various time scales will require integrating the new concept of nanoscale organization with our traditional molecular and trafficking views. Most likely, new conceptual advances will be required to gain a full understanding of the rules and mechanisms of synaptic plasticity. The subunit trafficking rules of AMPAR will need to be clarified and refined in view of the expanded diversity of AMPAR complexes
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We wish to acknowledge the critical suggestions of Angela Getz on this MS. We express our warmest thanks to the many outstanding members of our team and collaborators that participated to elaboration of these concepts. This work is currently supported by funding from the Ministère de l’Enseignement Supérieur et de la Recherche, Centre National de la Recherche Scientifique, ERC Grant #787340 Dyn-Syn-Mem, and the Conseil Régional de Nouvelle Aquitaine.
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