Regulation of Dendritic Spine Morphology by SPAR, a PSD-95-Associated RapGAP
TL;DR: It is reported that SPAR, a Rap-specific GTPase-activating protein (RapGAP), interacts with the guanylate kinase-like domain of PSD-95 and forms a complex with PSD -95 and NMDA receptors in brain.
About: This article is published in Neuron.The article was published on 2001-08-02 and is currently open access. It has received 387 citations till now. The article focuses on the topics: Dendritic spine morphogenesis & Dendritic spine.
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TL;DR: The results indicate that spines individually follow Hebb's postulate for learning and suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long- term memory.
Abstract: Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.
2,295 citations
Cites background from "Regulation of Dendritic Spine Morph..."
...However, the precise molecular mechanisms of F-actin reorganizatio...
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TL;DR: This work has reported the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity in the adult brain.
Abstract: The mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases-1 and -2 (ERK1 and ERK2) has a key role in the differentiation of some cell types and the proliferation of others. However, several recent reports implicate this cascade in the control of synaptic plasticity in the adult brain. ERK signalling seems to be essential for characterized neuronal transcriptional events, and might also regulate synaptic targets to control plasticity. Another recently emerging story is the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity.
1,396 citations
TL;DR: New insights into the molecular mechanisms that regulate spine morphogenesis offer potential ways to manipulate dendritic spines in vivo and to explore their physiological roles in the brain.
Abstract: Dendritic spines are tiny protrusions that receive excitatory synaptic input and compartmentalize postsynaptic responses. Heterogeneous in size and shape, and modifiable by activity and experience, dendritic spines have long been thought to provide a morphological basis for synaptic plasticity. Although advanced imaging techniques have highlighted the rapid and regulated motility of spines in living neurons, the functional significance of spine plasticity remains elusive. Recent insights into the molecular mechanisms that regulate spine morphogenesis offer potential ways to manipulate dendritic spines in vivo and to explore their physiological roles in the brain.
929 citations
TL;DR: In this paper, it was shown that large and small spines are "memory spines" and "learning spines", respectively, and that spine structure and the underlying organization of the actin cytoskeleton are major determinants of fast synaptic transmission and therefore are likely to provide a physical basis for memory in cortical neuronal networks.
816 citations
TL;DR: It is shown that Ras relays the NMDA-R and CaMKII signaling that drives synaptic delivery of AMPA-Rs during long-term potentiation, and Rap mediates NMda-R-dependent removal of synaptic AMpa-Rs that occurs duringLong-term depression.
772 citations
Cites background from "Regulation of Dendritic Spine Morph..."
...The Ras pathway enhances transmission by controlspine morphology (Pak et al., 2001)....
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...(Chen et al., 1998; Husi et al., 2000; Kim et al., 1998; Pak et al., 2001; Ye et al., 2000)....
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...…have been shown toUniversity of Virginia School of Medicine Charlottesville, Virginia 22908 control important neuronal functions (Dolmetsch et al., 2001; Pak et al., 2001; Wu et al., 2001; Ye et al., 2000) and have significant effects on behavior (Brambilla et al., 1997; Costa et al., 2002)....
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...Here, we provide a RapGAP (SPAR) at synapses (Pak et al., 2001)....
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References
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TL;DR: The yeast two-hybrid system was used to show that the cytoplasmic tails of NMDA receptor subunits interact with a prominent postsynaptic density protein PSD-95, which may affect the plasticity of excitatory synapses.
Abstract: The N-methyl-D-aspartate (NMDA) receptor subserves synaptic glutamate-induced transmission and plasticity in central neurons. The yeast two-hybrid system was used to show that the cytoplasmic tails of NMDA receptor subunits interact with a prominent postsynaptic density protein PSD-95. The second PDZ domain in PSD-95 binds to the seven-amino acid, COOH-terminal domain containing the terminal tSXV motif (where S is serine, X is any amino acid, and V is valine) common to NR2 subunits and certain NR1 splice forms. Transcripts encoding PSD-95 are expressed in a pattern similar to that of NMDA receptors, and the NR2B subunit co-localizes with PSD-95 in cultured rat hippocampal neurons. The interaction of these proteins may affect the plasticity of excitatory synapses.
1,895 citations
"Regulation of Dendritic Spine Morph..." refers background in this paper
...In heterologous cells, act with the C termini of NMDA receptor NR2 subunitsSPAR reorganizes the actin cytoskeleton and recruits (Kornau et al., 1995; Niethammer et al., 1996), whereasPSD-95 to F-actin....
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TL;DR: After induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrites or in slices where long-term potentiation was blocked, no significant spine growth occurred.
Abstract: Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.
1,749 citations
"Regulation of Dendritic Spine Morph..." refers background in this paper
..., 1999), and LTP-inducing stimuli Massachusetts General Hospital and can promote new spine formation via NMDA receptorHarvard Medical School dependent mechanisms (Engert and Bonhoeffer, 1999; Boston, Massachusetts 02114 Maletic-Savatic et al., 1999)....
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...…stimuliMassachusetts General Hospital and can promote new spine formation via NMDA receptor-Harvard Medical School dependent mechanisms (Engert and Bonhoeffer, 1999;Boston, Massachusetts 02114 Maletic-Savatic et al., 1999).2 Department of Biological Sciences What are the signaling…...
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TL;DR: Direct evidence is presented that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits.
Abstract: ACTIVATION of the N-methyl-d-aspartate (NMDA) receptor is important for certain forms of activity-dependent synaptic plasticity, such as long-term potentiation (reviewed in ref. 1), and the patterning of connections during development of the visual system (reviewed in refs 2, 3). Several subunits of the NMDA receptor have been cloned: these are NMDAR1 (NR1), and NMDAR2A, 2B, 2C and 2D (NR2A-D)4–8. Based on heterologous co-expression studies, it is inferred that NR1 encodes an essential subunit of NMDA receptors and that functional diversity of NMDA receptors in vivo is effected by differential incorporation of subunits NR2A–NR2D5–8. Little is known, however, about the actual subunit composition or heterogeneity of NMDA receptors in the brain. By co-immunoprecipitation with subunit-specific antibodies, we present here direct evidence that NMDA receptors exist in rat neocortex as heteromeric complexes of considerable heterogeneity, some containing both NR2A and NR2B subunits. A progressive alteration in subunit composition seen postnatally could contribute to NMDA-receptor variation and changing synaptic plasticity during cortical development.
1,328 citations
"Regulation of Dendritic Spine Morph..." refers background in this paper
...For all other quantitations, three to fourstone et al., 1992), NR2B (Sheng et al., 1994)....
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...In contrast, the F-actin cy-(NR2B) and SynGAP (Figure 1G, lane 4)....
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TL;DR: High-frequency focal synaptic stimulation induced a period of enhanced growth of small filopodia-like protrusions in dendritic regions close to the stimulating electrode and was prevented by blockade of N-methyl-D-aspartate receptors.
Abstract: Activity shapes the structure of neurons and their circuits. Two-photon imaging of CA1 neurons expressing enhanced green fluorescent protein in developing hippocampal slices from rat brains was used to characterize dendritic morphogenesis in response to synaptic activity. High-frequency focal synaptic stimulation induced a period (longer than 30 minutes) of enhanced growth of small filopodia-like protrusions (typically less than 5 micrometers long). Synaptically evoked growth was long-lasting and localized to dendritic regions close (less than 50 micrometers) to the stimulating electrode and was prevented by blockade of N-methyl-D-aspartate receptors. Thus, synaptic activation can produce rapid input-specific changes in dendritic structure. Such persistent structural changes could contribute to the development of neural circuitry.
1,263 citations
"Regulation of Dendritic Spine Morph..." refers background in this paper
...…promote new spine formation via NMDA receptor-Harvard Medical School dependent mechanisms (Engert and Bonhoeffer, 1999;Boston, Massachusetts 02114 Maletic-Savatic et al., 1999).2 Department of Biological Sciences What are the signaling pathways that link glutamateKorea Advanced Institute for…...
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TL;DR: Proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain indicates the NRC also participates in human cognition.
Abstract: N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.
1,210 citations
"Regulation of Dendritic Spine Morph..." refers background in this paper
...The func-coimmunoprecipitation (Husi et al., 2000)....
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...The relative distribution of spine shapes did not ap- synaptic proteins that includes NMDA receptors and their downstream signaling targets (Husi et al., 2000;pear to be affected by SPAR, with similar percentages of mushroom, stubby, and thin spines in GFP and SPAR Sheng and Pak, 2000; Walikonis et…...
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