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Acute Inactivation of PSD-95 Destabilizes AMPA Receptors at Hippocampal Synapses  [PDF]
Guillermo A. Yudowski, Olav Olsen, Hillel Adesnik, Kurt W. Marek, David S. Bredt
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053965
Abstract: Postsynatptic density protein (PSD-95) is a 95 kDa scaffolding protein that assembles signaling complexes at synapses. Over-expression of PSD-95 in primary hippocampal neurons selectively increases synaptic localization of AMPA receptors; however, mice lacking PSD-95 display grossly normal glutamatergic transmission in hippocampus. To further study the scaffolding role of PSD-95 at excitatory synapses, we generated a recombinant PSD-95-4c containing a tetracysteine motif, which specifically binds a fluorescein derivative and allows for acute and permanent inactivation of PSD-95. Interestingly, acute inactivation of PSD-95 in rat hippocampal cultures rapidly reduced surface AMPA receptor immunostaining, but did not affected NMDA or transferrin receptor localization. Acute photoinactivation of PSD-95 in dissociated neurons causes ~80% decrease in GluR2 surface staining observed by live-cell microscopy within 15 minutes of PSD-95-4c ablation. These results confirm that PSD-95 stabilizes AMPA receptors at postsynaptic sites and provides insight into the dynamic interplay between PSD-95 and AMPA receptors in live neurons.
SynDIG1 Promotes Excitatory Synaptogenesis Independent of AMPA Receptor Trafficking and Biophysical Regulation  [PDF]
Kathryn L. Lovero, Sabine M. Blankenship, Yun Shi, Roger A. Nicoll
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066171
Abstract: AMPA receptors–mediators of fast, excitatory transmission and synaptic plasticity in the brain–achieve great functional diversity through interaction with different auxiliary subunits, which alter both the trafficking and biophysical properties of these receptors. In the past several years an abundance of new AMPA receptor auxiliary subunits have been identified, adding astounding variety to the proteins known to directly bind and modulate AMPA receptors. SynDIG1 was recently identified as a novel AMPA receptor interacting protein that directly binds to the AMPA receptor subunit GluA2 in heterologous cells. Functionally, SynDIG1 was found to regulate the strength and density of AMPA receptor containing synapses in hippocampal neurons, though the way in which SynDIG1 exerts these effects remains unknown. Here, we aimed to determine if SynDIG1 acts as a traditional auxiliary subunit, directly regulating the function and localization of AMPA receptors in the rat hippocampus. We find that, unlike any of the previously characterized AMPA receptor auxiliary subunits, SynDIG1 expression does not impact AMPA receptor gating, pharmacology, or surface trafficking. Rather, we show that SynDIG1 regulates the number of functional excitatory synapses, altering both AMPA and NMDA receptor mediated transmission. Our findings suggest that SynDIG1 is not a typical auxiliary subunit to AMPA receptors, but instead is a protein critical to excitatory synaptogenesis.
GluA2-lacking AMPA receptors in hippocampal CA1 cell synapses: evidence from gene-targeted mice  [PDF]
Andrei Rozov,Peter H. Seeburg
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00022
Abstract: The GluA2 subunit in heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels restricts Ca2+ permeability and block by polyamines, rendering linear the current-voltage relationship of these glutamate-gated cation channels. Although GluA2-lacking synaptic AMPA receptors occur in GABA-ergic inhibitory neurons, hippocampal CA1 pyramidal cell synapses are widely held to feature only GluA2 containing AMPA receptors. A controversy has arisen from reports of GluA2-lacking AMPA receptors at hippocampal CA3-to-CA1 cell synapses and a study contesting these findings. Here we sought independent evidence for the presence of GluA2-lacking AMPA receptors in CA1 pyramidal cell synapses by probing the sensitivity of their gated cation channels in wild-type (WT) mice and gene-targeted mouse mutants to philanthotoxin, a specific blocker of GluA2-lacking AMPA receptors. The mutants either lacked GluA2 for maximal philanthotoxin sensitivity, or, for minimal sensitivity, expressed GluA1 solely in a Q/R site-edited version or not at all. Our comparative electrophysiological analyses provide incontrovertible evidence for the presence in wild-type CA1 pyramidal cell synapses of GluA2-less AMPA receptor channels. This article is part of a Special Issue entitled “Calcium permeable AMPARs in synaptic plasticity and disease.”
Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs
Thomas M Sanderson, Graham L Collingridge, Stephen M Fitzjohn
Molecular Brain , 2011, DOI: 10.1186/1756-6606-4-30
Abstract: AMPA receptor trafficking is under exquisite control in excitatory neurons (reviewed in [1,2]). One way to change the efficacy of a synapse is to redistribute AMPA receptors at the postsynaptic membrane so as to either increase or decrease their number and thus alter the responsiveness of the synapse to glutamate. Such changes in synaptic efficacy, termed synaptic plasticity, are crucial for normal brain function, particularly during the development of synaptic connections and memory formation. One form of plasticity, long term depression (LTD), involves a decrease in synaptic strength and can occur via trafficking of AMPA receptors away from synapses. Two major forms of LTD have been described in the CNS that are triggered by the activation of NMDA and mGluRs. These are induced physiologically by trains of electrical stimulation [3-5] but can also be mimicked by the application of specific agonists, in particular N-methyl D-aspartate (NMDA) [6,7] and dihydroxyphenylglycine DHPG [8-10], respectively.For NMDA-induced LTD there is agreement between electrophysiological and imaging studies on the importance of AMPA receptor endocytosis in LTD expression [1,3,11,12]. In the case of mGluR-induced LTD (mGluR-LTD), however, conflicting evidence has been reported [13]. Immunofluorescence and biochemical studies indicate that surface AMPA receptor numbers decrease on exposure to DHPG [14-16]. However, a range of electrophysiological measurements, such as changes in paired-pulse facilitation [14,17-20], failure rate [17], coefficient of variation [14,17] and mEPSC parameters [14,17], are more indicative of a presynaptic locus of expression. Consistent with this, recordings from adult hippocampal slices show no change in postsynaptic sensitivity to glutamate following DHPG-induced LTD [21] and in both adult and juvenile hippocampal slices the amount of stimulus-induced zinc exocytosis (a measure of neurotransmitter release) decreases as a result of DHPG-induced LTD [22]. A dev
Direct imaging of lateral movements of AMPA receptors inside synapses  [PDF]
Catherine Tardin,Laurent Cognet,Cécile Bats,Brahim Lounis,Daniel Choquet
Physics , 2007, DOI: 10.1093/emboj/cdg463
Abstract: Trafficking of AMPA receptors in and out of synapses is crucial for synaptic plasticity. Previous studies have focused on the role of endo/exocytosis processes or that of lateral diffusion of extra-synaptic receptors. We have now directly imaged AMPAR movements inside and outside synapses of live neurons using single-molecule fluorescence microscopy. Inside individual synapses, we found immobile and mobile receptors, which display restricted diffusion. Extra-synaptic receptors display free diffusion. Receptors could also exchange between these membrane compartments through lateral diffusion. Glutamate application increased both receptor mobility inside synapses and the fraction of mobile receptors present in a juxtasynaptic region. Block of inhibitory transmission to favor excitatory synaptic activity induced a transient increase in the fraction of mobile receptors and a decrease in the proportion of juxtasynaptic receptors. Altogether, our data show that rapid exchange of receptors between a synaptic and extra-synaptic localization occurs through regulation of receptor diffusion inside synapses.
Cortical development of AMPA receptor trafficking proteins  [PDF]
Kathryn M. Murphy,Lilia Tcharnaia,Simon P. Beshara,David G. Jones
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00065
Abstract: AMPA-receptor trafficking plays a central role in excitatory plasticity, especially during development. Changes in the number of AMPA receptors and time spent at the synaptic surface are important factors of plasticity that directly affect long-term potentiation (LTP), long-term depression (LTD), synaptic scaling, and the excitatory-inhibitory (E/I) balance in the developing cortex. Experience-dependent changes in synaptic strength in visual cortex (V1) use a molecularly distinct AMPA trafficking pathway that includes the GluA2 subunit. We studied developmental changes in AMPA receptor trafficking proteins by quantifying expression of GluA2, pGluA2 (GluA2serine880), GRIP1, and PICK1 in rat visual and frontal cortex. We used Western Blot analysis of synaptoneurosome preparations of rat visual and frontal cortex from animals ranging in age from P0 to P105. GluA2 and pGluA2 followed different developmental trajectories in visual and frontal cortex, with a brief period of over expression in frontal cortex. The over expression of GluA2 and pGluA2 in immature frontal cortex raises the possibility that there may be a period of GluA2-dependent vulnerability in frontal cortex that is not found in V1. In contrast, GRIP1 and PICK1 had the same developmental trajectories and were expressed very early in development of both cortical areas. This suggests that the AMPA-interacting proteins are available to begin trafficking receptors as soon as GluA2-containing receptors are expressed. Finally, we used all four proteins to analyze the surface-to-internalization balance and found that this balance was roughly equal across both cortical regions, and throughout development. Our finding of an exquisite surface-to-internalization balance highlights that these AMPA receptor trafficking proteins function as a tightly controlled system in the developing cortex.
The Ubiquitin Ligase RPM-1 and the p38 MAPK PMK-3 Regulate AMPA Receptor Trafficking  [PDF]
Eun Chan Park, Doreen R. Glodowski, Christopher Rongo
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004284
Abstract: Ubiquitination occurs at synapses, yet its role remains unclear. Previous studies demonstrated that the RPM-1 ubiquitin ligase organizes presynaptic boutons at neuromuscular junctions in C. elegans motorneurons. Here we find that RPM-1 has a novel postsynaptic role in interneurons, where it regulates the trafficking of the AMPA-type glutamate receptor GLR-1 from synapses into endosomes. Mutations in rpm-1 cause the aberrant accumulation of GLR-1 in neurites. Moreover, rpm-1 mutations enhance the endosomal accumulation of GLR-1 observed in mutants for lin-10, a Mint2 ortholog that promotes GLR-1 recycling from Syntaxin-13 containing endosomes. As in motorneurons, RPM-1 negatively regulates the pmk-3/p38 MAPK pathway in interneurons by repressing the protein levels of the MAPKKK DLK-1. This regulation of PMK-3 signaling is critical for RPM-1 function with respect to GLR-1 trafficking, as pmk-3 mutations suppress both lin-10 and rpm-1 mutations. Positive or negative changes in endocytosis mimic the effects of rpm-1 or pmk-3 mutations, respectively, on GLR-1 trafficking. Specifically, RAB-5(GDP), an inactive mutant of RAB-5 that reduces endocytosis, mimics the effect of pmk-3 mutations when introduced into wild-type animals, and occludes the effect of pmk-3 mutations when introduced into pmk-3 mutants. By contrast, RAB-5(GTP), which increases endocytosis, suppresses the effect of pmk-3 mutations, mimics the effect of rpm-1 mutations, and occludes the effect of rpm-1 mutations. Our findings indicate a novel specialized role for RPM-1 and PMK-3/p38 MAPK in regulating the endosomal trafficking of AMPARs at central synapses.
Regulation of AMPA receptors in spinal nociception
Yun Wang, Jing Wu, Zhiguo Wu, Qing Lin, Yun Yue, Li Fang
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-5
Abstract: Glutamate synapses are involved in most excitatory neurotransmission in the central nervous system (CNS). The major glutamate receptor subtypes at glutamatergic synapses are currently subdivided into ionotropic glutamate receptors (ion channel forming) and metabotropic glutamate receptors (G-protein coupled). The former may include N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, such as AMPA and kainite receptors. Cumulative evidence suggests that activity-dependent changes in the efficacy of glutamatergic synapses in pain transmission pathways greatly contribute to chronic pain caused by tissue damage or nerve injuries [1,2]. A great number of studies have addressed the role of NMDA receptors and metabotropic glutamate receptors in synapses between primary afferent fibers and spinal neurons. It has been demonstrated that the activation of NMDA receptors and metabotropic glutamate receptors critically contributed to the development of chronic nociceptive hypersensitivity following peripheral tissue damage or nerve injuries [1]. In contrast, the AMPA glutamate receptors are originally thought to mediate rapid excitatory neurotransmission in the CNS. Recently, more studies had supported the critical contributions of spinal AMPA receptors in the development of both acute and chronic painful responses [3-6].AMPA receptors are widely distributed in the CNS. The functional properties and regulations of AMPA receptors in different brain regions, such as in the hippocampus (during long-term potentiation) and the cerebellum (during long-term depression), have been well studied both in vitro and in vivo. These studies suggest that the glutamate-mediated excitatory synaptic transmission efficiency is dependent on the number and function of AMPA receptors at glutamatergic synapses. The former is associated with the trafficking of AMPA receptors and the latter, is influenced by AMPA receptor subunit composition, post-transcriptional and post-translational modificat
Insulin Age-Dependently Modulates Synaptic Transmission and AMPA Receptor Trafficking in Region CA1 of the Rat Hippocampus  [PDF]
Shayna A. Wrighten, Gerardo G. Piroli
Open Journal of Molecular and Integrative Physiology (OJMIP) , 2016, DOI: 10.4236/ojmip.2016.62003
Abstract: Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events that haven’t been studied in the mature rat hippocampus. In our studies, we used hippocampal preparations from juvenile (14 - 25 days) and mature (60 - 90 days) rats to assess insulin modulation of CA1 synaptic transmission and AMPAR trafficking and phosphorylation. Using field potential electrophysiology, we observed that insulin induced LTD in the juvenile hippocampus (as previously reported) in the presence and absence of phosphoinositide 3-kinase (PI3K) activity, but produced no significant long-term changes in the mature hippocampus in the presence of PI3K activity. Interestingly, during PI3K inhibition, insulin did produce LTD in the mature hippocampus. Additionally, insulin induced a long-term decrease in plasma membrane expression of the GluA2 and GluA1 subunits of the AMPAR in the juvenile, but not mature hippocampus. Furthermore, there was a long-term decrease in GluA1 phosphorylation at Serine 845 in the juvenile, but not mature hippocampus. These data reveal that insulin modulation of synaptic plasticity and AMPAR modulation within the hippocampus is age-dependent, suggesting that insulin-regulated behaviors may also show age-dependence. These findings are important largely due to the increased use of insulin as a therapeutic throughout the lifespan. Our data suggest that additional work should be done to determine how this use of insulin throughout different stages of life might affect synaptic function and development.
AMPA Receptor Trafficking in Homeostatic Synaptic Plasticity: Functional Molecules and Signaling Cascades  [PDF]
Guan Wang,James Gilbert,Heng-Ye Man
Neural Plasticity , 2012, DOI: 10.1155/2012/825364
Abstract: Homeostatic synaptic plasticity is a negative-feedback response employed to compensate for functional disturbances in the nervous system. Typically, synaptic activity is strengthened when neuronal firing is chronically suppressed or weakened when neuronal activity is chronically elevated. At both the whole cell and entire network levels, activity manipulation leads to a global up- or downscaling of the transmission efficacy of all synapses. However, the homeostatic response can also be induced locally at subcellular regions or individual synapses. Homeostatic synaptic scaling is expressed mainly via the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and synaptic expression. Here we review the recently identified functional molecules and signaling pathways that are involved in homeostatic plasticity, especially the homeostatic regulation of AMPAR localization at excitatory synapses. 1. Introduction The brain has the amazing ability to adapt through its capability to change in response to experience and use. This fundamental property of plasticity serves to learn and remember complex tasks, obtain rewards, or even recover after injury. Surprisingly, with constant dynamic changes occurring in the brain, neuronal activity remains stable over an entire lifespan. Our brains appear to be constructed in such a manner that the mechanisms involved in learning and memory can be balanced by another distinct form of neuronal modulation, homeostatic plasticity. These two forms of plasticity coexist to adapt to the changing sensory world while maintaining a balance of neural activity within a physiological range. Hebbian synaptic plasticity is associative and input specific, which strengthens or weakens the transmission efficacy of individual synapses. Long-term potentiation (LTP) and depression (LTD), the two best studied forms of Hebbian plasticity, are widely considered to be the cellular mechanisms for learning and memory. However, given the positive-feedback nature of Hebbian plasticity, this form of synaptic modulation could potentially result in synapses of either functional saturation or silence, driving the whole network into an unstable state if left unchecked. Hebbian synaptic plasticity therefore necessitates distinct homeostatic mechanisms that can stabilize a network in the face of constant dynamic changes in synaptic strength. Indeed, neuronal networks use an array of homeostatic negative-feedback mechanisms that allow neurons to assess their activity and adjust accordingly so as to restrain their
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