A developmental switch in the signaling cascades for LTP induction

Yasuda, Hiroki; Barth, Alison L.; Stellwagen, David; Malenka, Robert C.

doi:10.1038/nn985

Cited by 283 publications

(245 citation statements)

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“…T286A mutants have substantial deficits in synaptic strengthening induced by electrical stimulation (10)(11)(12)(13)(14). The expression of the IEGs Zif268 and c-Fos has been shown to be a prerequisite for late LTP (17,18).…”

Section: Resultsmentioning

confidence: 99%

“…As a proxy, here we have studied T286A missense mutant mice lacking autophosphorylation at threonine 286 of the α-isoform of calcium/calmodulindependent kinase II (αCaMKII), a major protein of glutamatergic synapses in the forebrain (11). The T286A mutants have fully blocked NMDA receptor-dependent synaptic strengthening at hippocampal CA1 synapses (11)(12)(13)(14), and they have impaired regulation of the postburst afterhyperpolarization (AHP) in CA1 pyramidal neurons (15). Accordingly, T286A mutants are deficient in contextual fear conditioning after a single training trial (16).…”

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confidence: 99%

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Mechanism for long-term memory formation when synaptic strengthening is impaired

Radwańska

Medvedev

Pereira

et al. 2011

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

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Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with traininginduced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.synaptic plasticity | hippocampus | immediate-early gene | reconsolidation A fundamental question in neuroscience concerns the cellular mechanisms that lead to long-term memory (LTM) formation (1-3). It has been shown that LTM formation is associated with and demands strengthening of existing synapses, socalled functional plasticity (3-5), but it may also be linked with a more overt form of structural plasticity, an increase in synapse density (6-9). It is, however, unclear whether de novo synaptogenesis is critical for LTM formation.The participation of synaptogenesis for LTM formation can be investigated when synaptic strengthening is fully blocked. It would be ideal to also block training-induced changes in neuronal excitability that have been implicated in memory formation (10). However, technically this block may not be achievable as, for example, there are distinct types of synaptic strengthening. As a proxy, here we have studied T286A missense mutant mice lacking autophosphorylation at threonine 286 of the α-isoform of calcium/calmodulindependent kinase II (αCaMKII), a major protein of glutamatergic synapses in the forebrain (11). The T286A mutants have fully blocked NMDA receptor-dependent synaptic strengthening at hippocampal CA1 synapses (11-14), and they have impaired regulation of the postburst afterhyperpolarization (AHP) in CA1 pyramidal neurons (15). Accordingly, T286A mutants are deficient in contextual fear conditioning after a single training trial (16). However, after five massed training trials, T286A mutants can form contextual LTM (16) and this type of LTM is hippocampus-dependent (14).Here, we have used T286A mutants as tools to investigate the mechanism of LTM formation when NMDA receptor-dependent synaptic strengthening is blocked. Our study provides evidence that activation of mTOR signaling in the hippocampus, followed by overexpression of PSD95 protein and...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Mechanism for long-term memory formation when synaptic strengthening is impaired

Radwańska

Medvedev

Pereira

et al. 2011

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

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“…There is now accumulating evidence that molecular mechanisms of LTP and LTD may differ in young versus adult hippocampus (Zamanillo et al, 1999, Jensen et al, 2003, Lee et al, 2003, Wikstrom et al, 2003, Yasuda et al, 2003, Palmer et al, 2004, Nosyreva and Huber, 2005. In particular, the involvement of GluR1 in LTP has been reported to occur only in adults (Zamanillo et al, 1999, Jensen et al, 2003.…”

Section: Normal Ltp and Ltd In Young "Penta" Phosphomutantsmentioning

confidence: 99%

Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors

Lee

Takamiya

Kameyama³

et al. 2007

Molecular and Cellular Neuroscience

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Phosphorylation of various AMPA receptor subunits can alter synaptic transmission and plasticity at excitatory glutamatergic synapses in the central nervous system. Here, we identified threonine-840 (T840) on the GluR1 subunit of AMPA receptors as a novel phosphorylation site. T840 is phosphorylated by protein kinase C (PKC) in vitro, and is a highly turned-over phosphorylation site in the hippocampus. Interestingly, the high basal phosphorylation of T840 in the hippocampus is maintained by a persistent activity of a protein kinase, which is counter-balanced by a basal protein phosphatase activity. To study the function of T840, we generated a line of mutant mice lacking this phosphorylation site using a gene knock-in technique. The mice generated lacks T840, in addition to two previously identified phosphorylation sites S831 and S845. Using this mouse, we demonstrate that T840 may regulate synaptic plasticity in an age-dependent manner.Many of the brain functions critically depend on plasticity of the glutamatergic excitatory synaptic transmission, which can be accomplished postsynaptically by modulation of glutamate receptors. AMPA-type glutamate receptors mediate the majority of fast excitatory synaptic transmission, and functional changes to these receptors are implicated in synaptic plasticity (Song and Huganir, 2002, Collingridge et al., 2004). One way to alter the function of AMPA receptors is by changing phosphorylation of its subunits. All four subunits of AMPA receptors, GluR1-4, which have several identified phosphorylation sites on their intracellular carboxy-terminus (Song and Huganir, 2002).Among the four subunits, GluR1 has three identified phosphorylation sites, serines 818 (S818) (Boehm et al., 2006), 831 (S831) and 845 (S845) (Roche et al., 1996). S831 is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), S845 is a cAMP-dependent protein kinase (PKA) substrate (Roche et al., 1996, Barria et al., 1997a, Mammen et al., 1997, while S818 is phosphorylated by PKC (Boehm et al., 2006). Changes in phosphorylation of GluR1 at S845 and S831 affect AMPA receptor mediated currents (Derkach et al., 1999, Banke et al., 2000, and are involved in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus (Barria et al., 1997b, Kameyama Correspondence to: Hey-Kyoung Lee. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. , Lee et al., 2003. Recent data suggests that S845 and S818 affect the trafficking AMPA receptors to synapses and/or stabilize synaptic AMPA receptors (Esteban et al., 2003,...

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“…Similar to other types of ionotropic glutamate receptors, synaptic recruitment of GluA4-containing AMPARs is regulated by interactions mediated by its C-terminal domain (CTD; Zhu et al, 2000;Boehm et al, 2006;Luchkina et al, 2014), which is a target for phosphorylation by PKA (Carvalho et al, 1999, Esteban et al, 2003. At GluA4 expressing developing synapses, PKA activation is both necessary and sufficient to drive AMPA receptors to synapses and to produce long-term potentiation (LTP) of synaptic transmission (Zhu et al, 2000;Esteban et al, 2003;Yasuda et al, 2003;Luchkina et al, 2014). This form of plasticity is restricted to early development (the first postnatal week in rodents), after which LTP becomes dependent on multiple kinases and, in particular, Ca 2+ /calmodulin dependent kinase II (CaMKII; e.g.…”

Section: Introductionmentioning

confidence: 99%

“…This form of plasticity is restricted to early development (the first postnatal week in rodents), after which LTP becomes dependent on multiple kinases and, in particular, Ca 2+ /calmodulin dependent kinase II (CaMKII; e.g. Yasuda et al, 2003). Here we have examined the molecular mechanism and physiological significance of the immature type GluA4-PKA dependent LTP.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

et al. 2017

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Synaptic recruitment of AMPA receptors (AMPARs) represents a key postsynaptic mechanism driving functional development and maturation of glutamatergic synapses. At immature hippocampal synapses, PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic reinforcement. However, the physiological significance and molecular determinants of this developmentally restricted form of plasticity are not known. Here we show that PKA activation leads to insertion of GluA4 to synaptic sites with initially weak or silent AMPAR-mediated transmission. This effect depends on a novel mechanism involving the extreme C-terminal end of GluA4, which interacts with the membrane proximal region of the C-terminal domain to control GluA4 trafficking. In the absence of GluA4, strengthening of AMPAR-mediated transmission during postnatal development was significantly delayed. These data suggest that the GluA4-mediated activation of silent synapses is a critical mechanism facilitating the functional maturation of glutamatergic circuitry during the critical period of experience-dependent fine-tuning.

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A developmental switch in the signaling cascades for LTP induction

Cited by 283 publications

References 15 publications

Mechanism for long-term memory formation when synaptic strengthening is impaired

Mechanism for long-term memory formation when synaptic strengthening is impaired

Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

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