Organelles and Trafficking Machinery for Postsynaptic Plasticity

Kennedy, Matthew J.; Ehlers, Michael

doi:10.1146/annurev.neuro.29.051605.112808

Cited by 307 publications

(276 citation statements)

References 231 publications

(286 reference statements)

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Section: Local Da Receptor Trafficking In Spinesmentioning

confidence: 99%

“…The confinement of receptors, which are mobile even within synapses, may be achieved by interactions with scaffolding proteins and other obstacles as well as by weak molecular interactions that act as steric hinderers or by inter-molecule attractive potentials. Single molecule tracking techniques have demonstrated that receptors can enter or exit the synapse via "lateral diffusion" through the perisynaptic space, providing a potential mechanism underlying changes in receptor number at the synapse [30]. The number of receptors within synapses under basal condition (the equilibrium set point) is determined by the number of scaffolding molecules and by cellular mechanisms that regulate the influx and efflux of receptors.…”

Section: Dynamic Trapping: a Potential Mechanism For Da Receptor Enrimentioning

confidence: 99%

“…In particular, extrasynaptic receptors may enter the synapse and integrate into the PSD, leading to long-term potentiation (LTP). Conversely, synaptic receptors may dissociate from the PSD and move to the extrasynaptic membrane, resulting in long-term depression (LTD) [28,30]. This dynamic trapping scheme, which is based primarily on studies of fast neurotransmitters (e.g.…”

Section: Dynamic Trapping: a Potential Mechanism For Da Receptor Enrimentioning

confidence: 99%

“…Larger cytoplasmic signaling molecules with slower diffusion coefficients (e.g. protein kinases and phosphatases) would be compartmentalized over longer periods of time.Membrane-bound receptors, such as N-methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs), can diffuse in the plasma membrane between synaptic and extrasynaptic compartments within spines [28], exchange between different spines [29], and undergo dynamic endocytotic and excytotic membrane trafficking within spines [30]. Recent studies demonstrate that spontaneous activity at individual spines can confine the diffusional movement of AMPA-type glutamate receptor subunit 1 (GluR1) to restricted submicron domains at single synapses, providing a novel mechanism of receptor compartmentalization which may directly contribute to synaptic plasticity [29].…”

mentioning

confidence: 99%

“…The localization of these endocytic zones suggests that spine components are internalized locally within spines. This local endocytic machinery may mediate the constitutive and activity-dependent trafficking of AMPARs in spines and may play a role in synaptic plasticity [30].Immunogold localization of D1 receptors in rat nucleus accumbens following administration of D1 agonists, however, reveals internalized D1 receptors associated with endocytic vesicles or endosomes in cell bodies and dendrites, but not spines [50]. In addition, snap shots of D2 receptor trafficking using high-resolution immunoelectron microscopy in the primate PFC have yet to capture any endocytosing or postendocytosing D2 receptors in spines; in contrast, clathrin-dependent endocytosis of D2 receptors in dendrites has been observed [51].…”

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confidence: 99%

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Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

107

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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Section: Local Da Receptor Trafficking In Spinesmentioning

confidence: 99%

Section: Dynamic Trapping: a Potential Mechanism For Da Receptor Enrimentioning

confidence: 99%

Section: Dynamic Trapping: a Potential Mechanism For Da Receptor Enrimentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

107

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TDP‐43 and FUS en route from the nucleus to the cytoplasm

Ederle¹,

2017

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Misfolded or mislocalized RNA‐binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TAR DNA‐binding protein of 43 kDa (TDP‐43) and fused in sarcoma (FUS), which form pathological messenger ribonucleoprotein aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP‐43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm. We discuss how TDP‐43 and FUS may exit the nucleus and how defects in both nuclear and cytosolic mRNA processing events, and possibly nuclear export defects, may contribute to neurodegeneration and ALS/FTD pathogenesis.

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A Phase I study of concurrent RMP‐7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

Packer

Krailo

Mehta

et al. 2005

Cancer

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BACKGROUNDNinety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP‐7 is a bradykinin analog that causes selective permeability of the blood‐brain‐tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP‐7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas.METHODSRMP‐7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment‐limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3–12 yrs).RESULTSOne child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose‐limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment.CONCLUSIONSThe results of this study confirmed the feasibility of giving RMP‐7 and carboplatin daily during radiotherapy to children with brainstem tumors. Cancer 2005. © 2005 American Cancer Society.

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Organelles and Trafficking Machinery for Postsynaptic Plasticity

Cited by 307 publications

References 231 publications

Dopaminergic signaling in dendritic spines

Dopaminergic signaling in dendritic spines

TDP‐43 and FUS en route from the nucleus to the cytoplasm

A Phase I study of concurrent RMP‐7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

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