Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors

Kim, Seonil; Ziff, Edward B.

doi:10.1371/journal.pbio.1001900

Cited by 107 publications

(195 citation statements)

References 63 publications

(110 reference statements)

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“…2D). Because CPARs exhibit a shorter decay time (21)(22)(23), this also indicated the presence of CPARs at KO synapses. We next used 20 μM 1-naphthyl acetyl spermine (naspm), a blocker of CPARs, to determine if CPARs were responsible for an increase of the amplitude in KO neurons ( Fig.…”

Section: Resultsmentioning

confidence: 98%

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Kim

Titcombe

Zhang

et al. 2015

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

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Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca 2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca 2+ -permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca 2+ -permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.LTP | Ca 2+ -permeable AMPA receptors | gene knockout | calcineurin

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Section: Resultsmentioning

confidence: 98%

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Kim

Titcombe

Zhang

et al. 2015

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

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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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“…A role for GluA1-S845 phosphorylation has also been proposed in the synaptic incorporation of CP-AMPARs during synaptic scaling. Cultures from knock-in mice harbouring the non-phosphorylatable S845A mutation 139 do not undergo TTXinduced synaptic upscaling. Moreover, TTX reduces calcineurin activity and upregulates phosphorylation of GluA1-S845, and inhibition of calcineurin mimics upscaling in the absence of TTX 139 .…”

Section: Ampar Phosphorylationmentioning

confidence: 97%

“…Cultures from knock-in mice harbouring the non-phosphorylatable S845A mutation 139 do not undergo TTXinduced synaptic upscaling. 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 .…”

Section: Ampar Phosphorylationmentioning

confidence: 97%

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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Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors

Cited by 107 publications

References 63 publications

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Synaptic AMPA receptor composition in development, plasticity and disease

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Calcineurin Mediates Synaptic Scaling Via Synaptic Trafficking of Ca2+-Permeable AMPA Receptors

Cited by 107 publications

References 63 publications

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca 2+ -permeable AMPA receptors

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca 2+ -permeable AMPA receptors

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Synaptic AMPA receptor composition in development, plasticity and disease

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Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors