Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

Horne, Eric A.; Dell’Acqua, Mark L.

doi:10.1523/jneurosci.4340-06.2007

Cited by 96 publications

(113 citation statements)

References 86 publications

(187 reference statements)

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“…11G-I ). It has been shown that neurons exposed to a chemical LTD protocol change spine morphology (Halpain et al, 1998;Horne and Dell'Acqua, 2007). Indeed, bath application of 50 M NMDA significantly decreased the number of spines, without affecting protrusion density (Fig.…”

Section: Eb3 Overexpresssion Protects Spines Against Ltd-induced Spinmentioning

confidence: 87%

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

Kapitein

Yau²,

Gouveia³

et al. 2011

J. Neurosci.

106

105

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Dynamic microtubules are important to maintain neuronal morphology and function, but whether neuronal activity affects the organization of dynamic microtubules is unknown. Here, we show that a protocol to induce NMDA-dependent long-term depression (LTD) rapidly attenuates microtubule dynamics in primary rat hippocampal neurons, removing the microtubule-binding protein EB3 from the growing microtubule plus-ends in dendrites. This effect requires the entry of calcium and is mediated by activation of NR2B-containing NMDA-type glutamate receptor. The rapid NMDA effect is followed by a second, more prolonged response, during which EB3 accumulates along MAP2-positive microtubule bundles in the dendritic shaft. MAP2 is both required and sufficient for this activity-dependent redistribution of EB3. Importantly, NMDA receptor activation suppresses microtubule entry in dendritic spines, whereas overexpression of EB3-GFP prevents NMDA-induced spine shrinkage. These results suggest that short-lasting and long-lasting changes in dendritic microtubule dynamics are important determinants for NMDA-induced LTD.

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Section: Eb3 Overexpresssion Protects Spines Against Ltd-induced Spinmentioning

confidence: 87%

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

Kapitein

Yau²,

Gouveia³

et al. 2011

J. Neurosci.

106

105

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“…The observation that NMDA application activates calcineurin and that the stimulatory effect of NMDA application on AMPA receptor endocytosis is blocked by calcineurin antagonists (47) is consistent with a model in which postsynaptic SJ1 is involved in mediating some of the effects of NMDA receptor activation. Interestingly, a recent study showed that decrease of PI(4,5)P 2 is required to trigger internalization of AMPA receptors in response to NMDA activation, and that inhibition of PLC, another manipulation that enhances PI(4,5)P 2 levels, impairs NMDA-induced AMPA receptor internalization and long-term depression (48).…”

Section: Discussionmentioning

confidence: 99%

Regulation of postsynaptic AMPA responses by synaptojanin 1

Gong

Camilli

2008

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

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Endocytosis of postsynaptic AMPA receptors is a mechanism through which efficiency of neurotransmission is regulated. We have genetically tested the hypothesis that synaptojanin 1, a phosphoinositide phosphatase implicated in the endocytosis of synaptic vesicles presynaptically, may also function in the endocytosis of AMPA receptors postsynaptically. Electrophysiological recordings of cultured hippocampal neurons showed that miniature excitatory postsynaptic current amplitudes were larger in synaptojanin 1 knockout (KO) neurons because of an increase of surface-exposed AMPA receptors. This change did not represent an adaptive response to decreased presynaptic release in KO cultures and was rescued by the expression of wild type, but not catalytically inactive synaptojanin 1, in the postsynaptic neuron. NMDAinduced internalization of pHluorin-tagged AMPA receptors (GluR2) was impaired in KO neurons. These results reveal a function of synaptojanin 1 in constitutive and triggered internalization of AMPA receptors and thus indicate a role for phosphatidylinositol(4,5)-bisphosphate metabolism in the regulation of postsynaptic AMPA responses.hree classes of ionotropic receptors-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and Nmethyl-D-aspartate (NMDA) receptors-mediate responses to glutamate, the major excitatory neurotransmitter, in the nervous system. AMPA receptors are responsible for most of the fast excitatory synaptic transmission (1). Therefore, alterations in AMPA receptor number and/or function at the synapse are likely to play an important role in synaptic plasticity and in learning and memory. AMPA receptors cycle constitutively by exoendocytosis between intracellular and surface-exposed pools, and the regulation of this cycle by signal molecules or synaptic activity allows for fast and effective control of receptor number on the postsynaptic membrane (2-5). For example, an increased number of surface-exposed AMPA receptors is a mechanism underlying long-term potentiation. Conversely, long-term depression may involve endocytosis of these receptors to reduce synaptic strength (2-4).Both constitutive and regulated AMPA receptor endocytosis were shown to be dependent on clathrin, the clathrin adaptors, and dynamin (3, 5-9). Thus, clathrin-mediated endocytosis, a process known to play a fundamental role in the recycling of synaptic vesicles (10, 11), also has a critical role postsynaptically, although the flux of endocytic traffic is much more intense presynaptically. Accordingly, a growing number of components of the clathrin-dependent endocytic machinery of the presynapse were reported, by either morphological or functional studies, to be present also at the postsynapse (8,9,12,13). One protein that is expressed at high levels in the nervous system and is concentrated in nerve terminals, where it has an important role in the clathrin-dependent recycling of synaptic vesicles, is synaptojanin 1 (SJ1) (14-17).SJ1 is a polyphosphoinositide phosphatase that mediates phosphatidylinositol(4...

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“…We previously reported that PSD-95 decreases dendrite branching by disrupting microtubule organization (Charych et al, 2006;Sweet et al, 2011a,b). Moreover, PSD-95 is in a complex with F-actin, and PSD-95 overexpression enhances dendritic spine formation and stabilization (Okabe et al, 1999;El-Husseini et al, 2000;Horne and Dell'Acqua, 2007). Cypin increases dendrite branching by promoting microtubule polymerization and negatively regulating PSD-95 clustering (Firestein et al, 1999;Akum et al, 2004;Charych et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure

Tseng¹,

Firestein²

2011

J. Neurosci.

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Focal swelling or varicosity formation in dendrites and loss of dendritic spines are the earliest indications of glutamate-induced excitotoxicity. Although it is known that microtubule dynamics play a role in varicosity formation, very little is known about the proteins that directly impact microtubules during focal swelling and dendritic spine loss. Our laboratory has recently reported that the postsynaptic protein PSD-95 and its cytosolic interactor (cypin) regulate the patterning of dendrites in hippocampal neurons. Cypin promotes microtubule assembly, and PSD-95 disrupts microtubule organization. Thus, we hypothesized that cypin and PSD-95 may play a role in altering dendrite morphology and spine number in response to sublethal NMDA-induced excitotoxicity. Using an in vitro model of glutamateinduced toxicity in rat hippocampal cultures, we found that cypin overexpression or PSD-95 knockdown increases the percentage of neurons with varicosities and the number of varicosities along dendrites, decreases the size of varicosities after sublethal NMDA exposure, and protects neurons from NMDA-induced death. In contrast, cypin knockdown or PSD-95 overexpression results in opposite effects. We further show that cypin regulates the density of spines/filopodia: cypin overexpression decreases the number of protrusions per micrometer of dendrite while cypin knockdown results in an opposite effect. Cypin overexpression and PSD-95 knockdown attenuate NMDA-promoted decreases in protrusion density. Thus, we have identified a novel pathway by which the microtubule cytoskeleton is regulated during sublethal changes to dendrites.

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Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

Cited by 96 publications

References 86 publications

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

NMDA Receptor Activation Suppresses Microtubule Growth and Spine Entry

Regulation of postsynaptic AMPA responses by synaptojanin 1

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure

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