NMDA Receptor Subunit-Dependent [Ca<sup>2</sup>+] Signaling in Individual Hippocampal Dendritic Spines

Sobczyk, Aleksander; Scheuss, Volker; Svoboda, Karel

doi:10.1523/jneurosci.1221-05.2005

Cited by 251 publications

(275 citation statements)

References 62 publications

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“…(i) The two types of structures and the two types of receptors at the PSD-NMDARs are generally located in the central region of the PSD, whereas AMPARs occupy the peripheral regions of the PSD (8,10). (ii) The number of AMPAR-type structures is positively correlated with PSD size, and the number of NMDARtype structures is independent of PSD size, in agreement with the results from other methods such as serial-section immuno-EM (8,10) and two-photon uncaging of glutamate on dendritic spines (69)(70)(71). (iii) The 176-nm diameter of the central NMDAR cluster at PSDs from this work matches the minimum PSD diameter of ∼180 nm for PSDs lacking AMPARs (8).…”

Section: Discussionsupporting

confidence: 85%

“…These distinguishing properties of AMPAR-and NMDAR-type structures matched the properties of AMPARs and NMDARs at the PSD shown by immuno-EM (8,10). Two-photon uncaging of glutamate on dendritic spines illustrated a similar dependence of AMPAR and NMDAR responses on spine size (69,70). Thus, AMPAR-type and NMDAR-type structures, as classified by EM tomography, are coextensive with AMPARs and NMDARs, respectively.…”

Section: Analysis Of Ampar-and Nmdar-type Structures By Em Tomographysupporting

confidence: 54%

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PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

Chen

Levy

Hou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

252

211

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The postsynaptic density (PSD)-95 family of membrane-associated guanylate kinases (MAGUKs) are major scaffolding proteins at the PSD in glutamatergic excitatory synapses, where they maintain and modulate synaptic strength. How MAGUKs underlie synaptic strength at the molecular level is still not well understood. Here, we explore the structural and functional roles of MAGUKs at hippocampal excitatory synapses by simultaneous knocking down PSD-95, PSD-93, and synapse-associated protein (SAP)102 and combining electrophysiology and transmission electron microscopic (TEM) tomography imaging to analyze the resulting changes. Acute MAGUK knockdown greatly reduces synaptic transmission mediated by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs). This knockdown leads to a significant rise in the number of silent synapses, diminishes the size of PSDs without changes in pre-or postsynaptic membrane, and depletes the number of membraneassociated PSD-95-like vertical filaments and transmembrane structures, identified as AMPARs and NMDARs by EM tomography. The differential distribution of these receptor-like structures and dependence of their abundance on PSD size matches that of AMPARs and NMDARs in the hippocampal synapses. The loss of these structures following MAGUK knockdown tracks the reduction in postsynaptic AMPAR and NMDAR transmission, confirming the structural identities of these two types of receptors. These results demonstrate that MAGUKs are required for anchoring both types of glutamate receptors at the PSD and are consistent with a structural model where MAGUKs, corresponding to membraneassociated vertical filaments, are the essential structural proteins that anchor and organize both types of glutamate receptors and govern the overall molecular organization of the PSD.T he postsynaptic density (PSD) at excitatory glutamatergic synapses, appearing in electron micrographs as a prominent electron-dense thickening lining the postsynaptic membrane (1) is a complex macromolecular machine positioned across from synaptic vesicle release sites at the presynaptic active zone. The PSD clusters and organizes neurotransmitter receptors and signaling molecules at the postsynaptic membrane, transmits and processes synaptic signals, and can undergo structural changes to encode and store information (2-5). Two types of ionotropic glutamate receptors, AMPA receptors (AMPARs) and NMDA receptors (NMDARs), present at PSDs of excitatory synapses (6-10) mediate almost all synaptic transmission in the brain (11). Biochemistry and mass spectrometry of the detergent-extracted cellular fraction of PSDs have additionally identified many proteins associated with AMPAR and NMDAR complexes (12, 13).The membrane-associated guanylate kinases (MAGUKs), a class of abundant scaffold proteins consisting of PSD-95, PSD-93, synapse-associated protein (SAP)102, and SAP97, interact directly with NMDARs (14-18). These MAGUK proteins share conserved modular structures consisting of three...

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Section: Discussionsupporting

confidence: 85%

Section: Analysis Of Ampar-and Nmdar-type Structures By Em Tomographysupporting

confidence: 54%

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

Chen

Levy

Hou

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

252

211

View full text Add to dashboard Cite

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“…org as supplemental material). However, there is no simple relation between spine depolarization and spine calcium levels: Number and subunit composition of NMDARs, as well as spine head volume, are heterogeneous, leading to differences in absolute calcium concentrations in individual spines even for identical EPSP amplitudes (Sobczyk et al, 2005). We developed an experimental protocol to compensate for this variability: Synaptically evoked calcium transients (CaTs) were measured under two conditions: Depolarized to the synaptic reversal potential in voltage clamp (here denoted as "0 mV") and free running (current clamp, denoted as "CC") ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Spine Neck Plasticity Controls Postsynaptic Calcium Signals through Electrical Compartmentalization

Grunditz¹,

Holbro²,

Tian³

et al. 2008

J. Neurosci.

141

173

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Dendritic spines have been proposed to function as electrical compartments for the active processing of local synaptic signals. However, estimates of the resistance between the spine head and the parent dendrite suggest that compartmentalization is not tight enough to electrically decouple the synapse. Here we show in acute hippocampal slices that spine compartmentalization is initially very weak, but increases dramatically upon postsynaptic depolarization. Using NMDA receptors as voltage sensors, we provide evidence that spine necks not only regulate diffusional coupling between spines and dendrites, but also control local depolarization of the spine head. In spines with high-resistance necks, presynaptic activity alone was sufficient to trigger calcium influx through NMDA receptors and R-type calcium channels. We conclude that calcium influx into spines, a key trigger for synaptic plasticity, is dynamically regulated by spine neck plasticity through a process of electrical compartmentalization.

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“…The precise mechanism by which the NR2A/NR2B ratio alters the plasticity threshold is currently unknown. It is possible that changes in the NR2A/ NR2B ratio regulate Ca 2ϩ influx through the NMDAR (Sobczyk et al, 2005;Sobczyk and Svoboda, 2007), or that the NR2A/NR2B ratio might regulate synaptic plasticity through changing the NR2A-and/or NR2B-associated downstream intracellular signaling molecules (Yashiro and Philpot, 2008).…”

Section: Metaplasticity Occurs When Pss Fail To Induce Persistent Chamentioning

confidence: 99%

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

Chen²,

Gu³

et al. 2009

Journal of Neuroscience

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In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold.

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NMDA Receptor Subunit-Dependent [Ca²+] Signaling in Individual Hippocampal Dendritic Spines

Cited by 251 publications

References 62 publications

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

Spine Neck Plasticity Controls Postsynaptic Calcium Signals through Electrical Compartmentalization

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

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NMDA Receptor Subunit-Dependent [Ca2+] Signaling in Individual Hippocampal Dendritic Spines

Cited by 251 publications

References 62 publications

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density

Spine Neck Plasticity Controls Postsynaptic Calcium Signals through Electrical Compartmentalization

Metaplastic Regulation of Long-Term Potentiation/Long-Term Depression Threshold by Activity-Dependent Changes of NR2A/NR2B Ratio

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NMDA Receptor Subunit-Dependent [Ca²+] Signaling in Individual Hippocampal Dendritic Spines