A Revised View on the Role of Surface AMPAR Mobility in Tuning Synaptic Transmission: Limitations, Tools, and Alternative Views

Delgado, Jary Y.; Selvin, Paul R

doi:10.3389/fnsyn.2018.00021

Cited by 10 publications

(6 citation statements)

References 63 publications

(176 reference statements)

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“…STED microscopy further showed that these morphological changes occurred both in vitro and in vivo (Hruska et al, 2018; Wegner et al, 2018). The dynamics of SSDs are in agreement with the exchange of individual proteins at synaptic and extra-synaptic sites, which is a hallmark of the dynamic synapse (Choquet and Triller, 2013; Delgado and Selvin, 2018). Therefore, SSDs are momentary representations of the protein distribution and need to be viewed as dynamic snapshots rather than rigid structural units.…”

Section: What Is a Subsynaptic Domain?supporting

confidence: 61%

Subsynaptic Domains in Super-Resolution Microscopy: The Treachery of Images

Yang

Specht

2019

Front. Mol. Neurosci.

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The application of super-resolution optical microscopy to investigating synaptic structures has revealed a highly heterogeneous and variable intra-synaptic organization. Dense subsynaptic protein assemblies named subsynaptic domains or SSDs have been proposed as structural units that regulate the efficacy of neuronal transmission. However, an in-depth characterization of SSDs has been hampered by technical limitations of super-resolution microscopy of synapses, namely the stochasticity of the signals during the imaging procedures and the variability of the synaptic structures. Here, we synthetize the available evidence for the existence of SSDs at central synapses, as well as the possible functional relevance of SSDs. In particular, we discuss the possible regulation of co-transmission at mixed inhibitory synapses as a consequence of the subsynaptic distribution of glycine receptors (GlyRs) and GABA A receptors (GABA A Rs). LAY ABSTRACT Super-resolution imaging strategies bypass the resolution limit of conventional optical microscopy and have given new insights into the distribution of proteins at synapses in the central nervous system. Neurotransmitter receptors and scaffold proteins appear to occupy specialized locations within synapses that we refer to as subsynaptic domains or SSDs. Interestingly, these SSDs are highly dynamic and their formation seems to be related to the remodeling of synapses during synaptic plasticity. It was also shown that SSDs of pre-and post-synaptic proteins are aligned in so-called nanocolumns, highlighting the role of SSDs in the regulation of synaptic transmission. Despite recent advances, however, the detection of SSDs with super-resolution microscopy remains difficult due to the inherent technical limitations of these approaches that are discussed in this review article.

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Section: What Is a Subsynaptic Domain?supporting

confidence: 61%

Subsynaptic Domains in Super-Resolution Microscopy: The Treachery of Images

Yang

Specht

2019

Front. Mol. Neurosci.

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“…However, recovery from MK-801 blockade has not been observed in hippocampal slices (Harris and Pettit 2007), a more physiologically relevant system. In addition, the use of quantum dots to label synaptic single molecules has been called into question because of their size and accessibility to synaptic space (Delgado and Selvin 2018). In this study we used MK-801 blockade of synaptic receptors in organotypic hippocampal slices to study whether NMDARs are able to diffuse in the plane of the membrane entering and leaving synaptic areas.…”

Section: Discussionmentioning

confidence: 99%

“…It was concluded that extrasynaptic and synaptic NMDARs form stable pools (Harris and Pettit 2007). In addition, questions regarding whether quantum dots used for single-molecule tracking can reliably access the synaptic space makes previous observations of rapid lateral diffusion of synaptic receptors using this method of tracking unclear (Delgado and Selvin 2018).…”

Section: Introductionmentioning

confidence: 99%

Rapid exchange of synaptic and extrasynaptic NMDA receptors in hippocampal CA1 neurons

McQuate

Barría

2020

Journal of Neurophysiology

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N-methyl-d-aspartate receptors (NMDARs) are fundamental coincidence detectors of synaptic activity necessary for the induction of synaptic plasticity and synapse stability. Adjusting NMDAR synaptic content, whether by receptor insertion or lateral diffusion between extrasynaptic and synaptic compartments, could play a substantial role defining the characteristics of the NMDAR-mediated excitatory postsynaptic current (EPSC), which in turn would mediate the ability of the synapse to undergo plasticity. Lateral NMDAR movement has been observed in dissociated neurons; however, it is currently unclear whether NMDARs are capable of lateral surface diffusion in hippocampal slices, a more physiologically relevant environment. To test for lateral mobility in rat hippocampal slices, we rapidly blocked synaptic NMDARs using MK-801, a use-dependent and irreversible NMDAR blocker. Following a 5-min washout period, we observed a strong recovery of NMDAR-mediated responses. The degree of the observed recovery was proportional to the amount of induced blockade, independent of levels of intracellular calcium, and mediated primarily by GluN2B-containing NMDA receptors. These results indicate that lateral diffusion of NMDARs could be a mechanism by which synapses rapidly adjust parameters to fine-tune synaptic plasticity. NEW & NOTEWORTHY N-methyl-d-aspartate-type glutamate receptors (NMDARs) have always been considered stable components of synapses. We show that in rat hippocampal slices synaptic NMDARs are in constant exchange with extrasynaptic receptors. This exchange of receptors is mediated primarily by NMDA receptors containing GluN2B, a subunit necessary to undergo synaptic plasticity. Thus this lateral movement of synaptic receptors allows synapses to rapidly regulate the total number of synaptic NMDARs with potential consequences for synaptic plasticity.

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“…2A-B, D). However, high concentration of SA (50 nM of free SA or 500 nM of SA-dye conjugates) has been shown to crosslink surface AMPARs and other proteins ( 12, 22 ); therefore, we used much lower concentration of SA-Atto647N (0.6 nM) (Fig. 2, 3), which we have previously verified not to induce cross-linking of AMPARs ( 4 ).…”

Section: Resultsmentioning

confidence: 99%

Single molecule tracking of AMPA receptors shows the role of synaptic insertion during maintenance of chemical LTP

Jin

Jang

et al. 2021

Preprint

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Long term potentiation (LTP) likely contributes to memory formation. Early expression of LTP involves insertion of AMPA receptors (AMPARs) to the extrasynaptic membrane followed by their lateral diffusion into the synaptic membrane. However, whether a similar mechanism mediates the maintenance of LTP is unclear. Using single-molecule microscopy, we quantified that 6 GluA1- and 11 GluA2-containing endogenous AMPARs were added per synapse in cultured hippocampal neurons at 20 min following chemical LTP (cLTP) induction for 10 min, resulting in a 54% increase for both subunits. Single molecular tracking of transfected subunits revealed that the number of exocytosed subunits at the synapse increased by 15-18% from 5 to 20 min following cLTP induction, but their lateral exchange between synaptic and extrasynaptic membranes was minimal. These findings suggest that cLTP maintenance is contributed largely by synaptic insertion of AMPARs rather than the surface diffusion of exocytosed AMPARs from extrasynaptic to synaptic regions.

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A Revised View on the Role of Surface AMPAR Mobility in Tuning Synaptic Transmission: Limitations, Tools, and Alternative Views

Cited by 10 publications

References 63 publications

Subsynaptic Domains in Super-Resolution Microscopy: The Treachery of Images

Subsynaptic Domains in Super-Resolution Microscopy: The Treachery of Images

Rapid exchange of synaptic and extrasynaptic NMDA receptors in hippocampal CA1 neurons

Single molecule tracking of AMPA receptors shows the role of synaptic insertion during maintenance of chemical LTP

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