Dataset Information

Linking Nanoscale Dynamics of AMPA Receptor Organization to Plasticity of Excitatory Synapses and Learning.

ABSTRACT: The spatiotemporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus of information processing by the brain. The ionotropic AMPA subtype of glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission in the CNS. The number of AMPARs located en face presynaptic glutamate release sites sets the efficacy of synaptic transmission. Understanding how this number is set and regulated has been the topic of intense research in the last two decades. We showed that AMPARs are not stable in the synapse as initially thought. They continuously enter and exit the postsynaptic density by lateral diffusion, and they exchange between the neuronal surface and intracellular compartments by endocytosis and exocytosis at extrasynaptic sites. Regulation of these various trafficking pathways has emerged as a key mechanism for activity-dependent plasticity of synaptic transmission, a process important for learning and memory. I here present my view of these findings. In particular, the advent of super-resolution microscopy and single-molecule tracking has helped to uncover the intricacy of AMPARs' dynamic organization at the nanoscale. In addition, AMPAR surface diffusion is highly regulated by a variety of factors, including neuronal activity, stress hormones, and neurodegeneration, suggesting that AMPAR diffusion-trapping may play a central role in synapse function. Using innovative tools to understand further the link between receptor dynamics and synapse plasticity is now unveiling new molecular mechanisms of learning. Modifying AMPAR dynamics may emerge as a new target to correct synapse dysfunction in the diseased brain.

SUBMITTER: Choquet D

PROVIDER: S-EPMC6705996 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Linking Nanoscale Dynamics of AMPA Receptor Organization to Plasticity of Excitatory Synapses and Learning.

Choquet Daniel D

The Journal of neuroscience : the official journal of the Society for Neuroscience 20181001 44

The spatiotemporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus of information processing by the brain. The ionotropic AMPA subtype of glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission in the CNS. The number of AMPARs located en face presynaptic glutamate release sites sets the efficacy of synaptic transmission. Understanding how this number is set and regulated has been the topic o ...[more]

PMID: 30381423

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Project description:A key feature of excitatory synapses is the existence of subsynaptic protein nanoclusters whose precise alignment across the cleft in a trans-synaptic nanocolumn influences the strength of synaptic transmission. However, whether nanocolumn properties vary between excitatory synapses functioning in different cellular contexts is unknown. We used a combination of confocal and DNA-PAINT super-resolution microscopy to directly compare the organization of shared scaffold proteins at two important excitatory synapses - those forming onto excitatory principal neurons (Ex→Ex synapses) and those forming onto parvalbumin-expressing interneurons (Ex→PV synapses). As in Ex→Ex synapses, we find that in Ex→PV synapses presynaptic Munc13-1 and postsynaptic PSD-95 both form nanoclusters that demonstrate alignment, underscoring synaptic nanostructure and the trans-synaptic nanocolumn as conserved organizational principles of excitatory synapses. Despite the general conservation of these features, we observed specific differences in the characteristics of pre- and postsynaptic Ex→PV nanostructure. Ex→PV synapses contained larger PSDs with fewer PSD-95 NCs when accounting for size than Ex→Ex synapses. Furthermore, the PSD-95 NCs were larger and denser. The identity of the postsynaptic cell also had a retrograde impact on Munc13-1 organization, as Ex→PV synapses hosted larger Munc13-1 puncta that contained less dense but larger and more numerous Munc13-1 NCs. Moreover, we measured the spatial variability of transsynaptic alignment in these synapse types, revealing protein alignment in Ex→PV synapses over a distinct range of distances compared to Ex→Ex synapses. We conclude that while general principles of nanostructure and alignment are shared, cell-specific elements of nanodomain organization likely contribute to functional diversity of excitatory synapses. Understanding the rules of synapse nanodomain assembly, which themselves are cell-type specific, will be essential for illuminating brain network dynamics.

Dataset Information

Linking Nanoscale Dynamics of AMPA Receptor Organization to Plasticity of Excitatory Synapses and Learning.

Publications

Linking Nanoscale Dynamics of AMPA Receptor Organization to Plasticity of Excitatory Synapses and Learning.

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