AMPA Receptors

Striessnig, Jörg; Watson, Jake F.; Greger, Ingo H.

doi:10.1002/9780470015902.a0029223

“…In particular, the number of AMPARs, α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, at the postsynaptic density (PSD) modulates the sensitivity of the synapse to presynaptic glutamate release, effectively tuning the synaptic connection strength [3, 4]. Since AMPAR is an important indicator of synaptic plasticity, specifically long-term potentiation (LTP) and long-term depression (LTD), it is vital to understand the role played by different factors to regulate AMPAR number density [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal modeling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

Bell

¹

,

Lee

²

,

Rangamani

³

2022

Preprint

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The modification of neural circuits depends on the strengthening and weakening of synaptic connections. Synaptic strength is often correlated to the density of the ionotropic, glutamateric receptors, AMPAR, (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) at the postsynaptic density (PSD). While AMPAR density is known to change based on complex biological signaling cascades, the effect of geometric factors such as dendritic spine shape, size, and curvature remain poorly understood. In this work, we developed a deterministic, spatiotemporal model to study the dynamics of AMPAR during long term potentiation (LTP). This model includes a minimal set of biochemical events that represent the upstream signaling events, trafficking of AMPAR to and from the PSD, lateral diffusion in the plane of the spine membrane, and the presence of an extrasynaptic AMPAR pool. Using idealized and realistic spine geometries, we show that the dynamics and increase of bound AMPAR at the PSD depends on a combination of endo- and exocytosis, membrane diffusion, availability of free AMPAR, and intracellular signaling interactions. We also found non-monotonic relationships between spine volume and change in AMPAR at the PSD, suggesting that spines restrict changes in AMPAR to optimize resources and prevent runaway potentiation.

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“…In particular, the number of AMPARs, α‐amino‐3‐hydroxy‐5‐methyl 4‐isoxazolepropionic acid receptors, at the postsynaptic density (PSD) modulates the sensitivity of the synapse to presynaptic glutamate release, effectively tuning the synaptic connection strength (Choquet, 2018; Park, 2018). Since AMPARs are an important indicator of synaptic plasticity, specifically long‐term potentiation (LTP) and long‐term depression, it is vital to understand the role played by different factors to regulate AMPAR density (Czöndör et al., 2012; Pinggera et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal modelling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

Bell

¹

,

Lee

²

,

Rangamani

³

2022

The Journal of Physiology

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The modification of neural circuits depends on the strengthening and weakening of synaptic connections. Synaptic strength is often correlated to the density of the ionotropic, glutamatergic receptors, AMPARs, (α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors) at the postsynaptic density (PSD). While AMPAR density is known to change based on complex biological signalling cascades, the effect of geometric factors such as dendritic spine shape, size and curvature remain poorly understood. In this work, we developed a deterministic, spatiotemporal model to study the dynamics of AMPARs during long‐term potentiation (LTP). This model includes a minimal set of biochemical events that represent the upstream signalling events, trafficking of AMPARs to and from the PSD, lateral diffusion in the plane of the spine membrane, and the presence of an extrasynaptic AMPAR pool. Using idealized and realistic spine geometries, we show that the dynamics and increase of bound AMPARs at the PSD depends on a combination of endo‐ and exocytosis, membrane diffusion, the availability of free AMPARs and intracellular signalling interactions. We also found non‐monotonic relationships between spine volume and the change in AMPARs at the PSD, suggesting that spines restrict changes in AMPARs to optimize resources and prevent runaway potentiation. Key points Synaptic plasticity involves dynamic biochemical and physical remodelling of small protrusions called dendritic spines along the dendrites of neurons. Proper synaptic functionality within these spines requires changes in receptor number at the synapse, which has implications for downstream neural functions, such as learning and memory formation. In addition to being signalling subcompartments, spines also have unique morphological features that can play a role in regulating receptor dynamics on the synaptic surface. We have developed a spatiotemporal model that couples biochemical signalling and receptor trafficking modalities in idealized and realistic spine geometries to investigate the role of biochemical and biophysical factors in synaptic plasticity. Using this model, we highlight the importance of spine size and shape in regulating bound AMPA receptor dynamics that govern synaptic plasticity, and predict how spine shape might act to reset synaptic plasticity as a built‐in resource optimization and regulation tool.

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AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions

Watson

¹

,

Striessnig

²

,

Ho

³

et al. 2021

Self Cite

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AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings from mouse hippocampal slices and super-resolution imaging in dissociated cultures, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.

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AMPA Receptors

Cited by 3 publications

References 68 publications

Spatiotemporal modeling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

Spatiotemporal modeling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

Spatiotemporal modelling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions

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