PKA-GluA1 Coupling via AKAP5 Controls AMPA Receptor Phosphorylation and Cell-Surface Targeting during Bidirectional Homeostatic Plasticity

Diering, Graham H.; Gustina, Ahleah S.; Huganir, Richard L.

doi:10.1016/j.neuron.2014.09.024

Cited by 131 publications

(189 citation statements)

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“…As expected, WT neurons exhibited a significant reduction in surface GluA1, GluA2, and GluA3 in response to bicuculline treatment ( Fig. 3 A-D) (9,26). Conversely, TTX-induced inactivity caused a significant increase in surface GluA1 and GluA2 with no change in surface GluA3 (Fig.…”

Section: Inactivity-induced Synaptic Scaling Is Blocked In Grip Knockoutsupporting

confidence: 73%

“…Several molecules involved in signaling or receptor trafficking are important or required for scaling up, such as AKAP5, PICK1, and Arc (9,11,16), are dispensable for scaling down. Conversely, molecules like Plk2 and PSD-93, though essential for downscaling, are not required for upscaling (15,40).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, the mechanisms of homeostatic regulation of AMPARs are currently under intense scrutiny. AMPAR trafficking is highly dynamic and regulated by binding partners and posttranslational modifications (5, 7) including phosphorylation (8,9). AMPAR trafficking, binding, and modification are highly subunit-specific.…”

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confidence: 99%

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GRIP1 is required for homeostatic regulation of AMPAR trafficking

Tan

Queenan

Huganir

2015

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

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Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms underlying the homeostatic regulation of AMPARs remain elusive. Here, we show that the expression of GRIP1, a multi-PDZ (postsynaptic density 95/discs large/zona occludens) domain AMPAR-binding protein, is bidirectionally altered by neuronal activity. Furthermore, we observe a subcellular redistribution of GRIP1 and a change in the binding of GRIP1 to GluA2 during synaptic scaling. Using a combination of biochemical, genetic, and electrophysiological methods, we find that loss of GRIP1 blocks the accumulation of surface AMPARs and the scaling up of synaptic strength that occur in response to chronic activity blockade. Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced synaptic scaling.synaptic scaling | postsynaptic density | glutamate receptor | PDZ domain

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Section: Inactivity-induced Synaptic Scaling Is Blocked In Grip Knockoutsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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GRIP1 is required for homeostatic regulation of AMPAR trafficking

Tan

Queenan

Huganir

2015

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

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“…Moreover, TTX reduces calcineurin activity and upregulates phosphorylation of GluA1-S845, and inhibition of calcineurin mimics upscaling in the absence of TTX 139 . Consistent with this, during TTX-induced scaling active PKA is enriched at synapses to mediate phosphorylation of GluA1 S845 and this process also requires the involvement of AKAP150 140 . Together, these data highlight the critical importance of GluA1-S845 phosphorylation in controlling the availability of synaptic CP-AMPARs.…”

Section: Ampar Phosphorylationsupporting

confidence: 64%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…PKA-mediated phosphorylation of GluA1 S845 has been shown to promote plasma membrane insertion of GluA1 and synaptic retention, thereby facilitating LTP (12,(39)(40)(41)(42)(43), whereas dephosphorylation of S845 by CaN and other phosphatases has been correlated with AMPAR endocytosis and LTD (11,12,40,42). In addition, it has been suggested that regulation of GluA1 S845 phosphorylation by PKA and CaN is involved in AMPAR trafficking during bidirectional homeostatic synaptic plasticity in cortical neurons (44,45; but see ref. 46).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Arendt

Zhang

Ganesan

et al. 2015

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

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Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

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PKA-GluA1 Coupling via AKAP5 Controls AMPA Receptor Phosphorylation and Cell-Surface Targeting during Bidirectional Homeostatic Plasticity

Cited by 131 publications

References 50 publications

GRIP1 is required for homeostatic regulation of AMPAR trafficking

GRIP1 is required for homeostatic regulation of AMPAR trafficking

Synaptic AMPA receptor composition in development, plasticity and disease

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

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