Rapid Functional Maturation of Nascent Dendritic Spines

Zito, Karen; Scheuss, Volker; Knott, Graham; Hill, Travis C.; Svoboda, Karel

doi:10.1016/j.neuron.2008.10.054

Cited by 246 publications

(220 citation statements)

References 72 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: 83%

“…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 Tomographymentioning

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

201

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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: 83%

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

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

201

View full text Add to dashboard Cite

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“…Uncaging of MNI-glutamate was achieved as previously described (49). In brief, the LFU stimulus consisted of 90 pulses (720 nm; 6-8 mW at the sample) of 1-ms duration delivered at 0.1 Hz by parking the beam at a point ∼0.5 μm from the center of the spine head.…”

Section: Methodsmentioning

confidence: 99%

Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening

Hill

Zito

2012

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

Self Cite

150

149

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Refinement of neural circuits in the mammalian cerebral cortex shapes brain function during development and in the adult. However, the signaling mechanisms underlying the synapse-specific shrinkage and loss of spiny synapses when neural circuits are remodeled remain poorly defined. Here, we show that low-frequency glutamatergic activity at individual dendritic spines leads to synapse-specific synaptic weakening and spine shrinkage on CA1 neurons in the hippocampus. We found that shrinkage of individual spines in response to lowfrequency glutamate uncaging is saturable, reversible, and requires NMDA receptor activation. Notably, shrinkage of large spines additionally requires signaling through metabotropic glutamate receptors (mGluRs) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs), supported by higher levels of mGluR signaling activity in large spines. Our results support a model in which signaling through both NMDA receptors and mGluRs is required to drive activity-dependent synaptic weakening and spine shrinkage at large, mature dendritic spines when neural circuits undergo experience-dependent modification.two-photon microscopy | long-term depression | synaptic plasticity | spine dynamics S tructural plasticity of neurons, such as the growth and retraction of dendritic spines, is thought to contribute to the experience-dependent changes in brain circuitry that mediate learning and memory (1, 2). In particular, the destabilization and loss of spiny synapses plays a critical role in the refinement of neural circuits during development and during learning. Indeed, spine elimination occurs more frequently than does spine formation in young rodents between the first and the third month of age (3-5), a period when experience-dependent refinement of neural circuitry is in its peak. Furthermore, several in vivo studies demonstrate that manipulations leading to experience-dependent circuit plasticity also increase the rate of spine shrinkage and loss (6-9). However, it remains unclear how neural activity drives the selective shrinkage and loss of individual dendritic spines in response to sensory experience.Dendritic spines occur in a wide variety of shapes and sizes (10, 11), and their stability is strongly correlated with spine size (3, 12, 13). Small spines are in general more motile and thought to serve as substrates for plasticity, or "learning" spines; large spines are more stable and thought to serve as components of functioning neural circuits, or "memory" spines (12,14). It is the selective shrinkage and loss of individual circuit-incorporated, persistent spines that underlies experience-dependent circuit refinement (6, 9, 15). Thus, experience-dependent circuit remodeling requires an activity-dependent mechanism that selectively induces shrinkage and retraction of those specific individual dendritic spines that are no longer useful for circuit function.Previous studies have established that low-frequency glutamatergic stimulation (LFS), which causes long-term depression (LTD) of synaptic transmission in...

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“…Such delays may differ among learning protocols and systems involved. Thus, some studies have suggested that synapses involving new spines or filopodia are assembled within the first 1-3 hours after potentiation 101 , whereas other studies have provided evidence for delays of 12-18 hours 102 . The longer delays provide a potential mechanism to relate learning to the consolidation of memories, for example, during sleep.…”

Section: Is It Inhibition or Excitation?mentioning

confidence: 99%

Structural plasticity upon learning: regulation and functions

2012

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The contributions of brain networks to information processing and learning and memory are classically interpreted within the framework of Hebbian plasticity and the notion that synaptic weights can be modified by specific patterns of activity. However, accumulating evidence over the past decade indicates that synaptic networks are also structurally plastic, and that connectivity is remodelled throughout life, through mechanisms of synapse formation, stabilization and elimination 1. This has led to the concept of structural plasticity, which can encompass a variety of morphological changes that have functional consequences. These include on the one hand structural rearrangements at pre-existing synapses, and on the other hand the formation or loss of synapses, of neuronal processes that form synapses or of neurons. In this Review we focus on plasticity that involves gains and/or losses of synapses. Its key potential implication for learning and memory is to physically alter circuit connectivity, thus providing long-lasting memory traces that can be recruited at subsequent retrieval. Detecting this form of plasticity and relating it to its possible functions poses unique challenges, which are in part due to our still limited understanding of how structure relates to function in the nervous system.We review recent studies that relate the structural plasticity of neuronal circuits to behavioural learning and memory and discuss conceptual and mechanistic advances, as well as future challenges. The studies establish a number of strong links between specific behavioural learning processes and the assembly and loss of specific synapses. Further areas of substantial progress include molecular and cellular mechanisms that regulate synapse dynamics in response to alterations in synaptic activity, the specific spatial distribution of the syn aptic changes among identified neurons and dendrites and the relative roles of excitation and inhibition in regulating structural plasticity.The new findings provide exciting early vistas of how learning and memory may be implemented at the level of structural circuit plasticity. At the same time, they highlight major gaps in our understanding of plasticity regulation at the cellular, circuit and systems levels. Accordingly, achieving a better mechanistic understanding of learning and memory processes is likely to depend on the development of more effective techniques and models to investigate ensembles of identified synapses longitudinally, both functionally and structurally. Molecular mechanisms of synapse remodellingA remarkable feature of excitatory and inhibitory synapses is their high level of structural variability 2 and the fact that their morphologies and stabilities change over time 3 . This phenomenon is regulated by activity, and the size of spine heads correlates with synaptic strength 4 , presynaptic properties 5 and the long-term stability of the synapse 6 . The morphological characteristics of synapses thus reveal important features of their function and stabilit...

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Rapid Functional Maturation of Nascent Dendritic Spines

Cited by 246 publications

References 72 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

Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening

Structural plasticity upon learning: regulation and functions

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