Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

Duffy, Steven; Nguyen, Peter V.

doi:10.1523/jneurosci.23-04-01142.2003

Cited by 64 publications

(56 citation statements)

References 66 publications

(127 reference statements)

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“…However, PKA is of particular interest in the delivery of AMPARs to extrasynaptic regions, because phosphorylation of the PKA site of GluR1 has been suggested to drive the delivery of AMPARs to extrasynaptic sites (31,32). To test whether PKA is required for the delivery of perisynaptic AMPARs, we loaded the postsynaptic neurons with the peptide inhibitor PKI (20 M) (33). PKI also led to a significant reduction in LTP ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

Yang

Wang

Frerking

et al. 2008

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

132

126

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Trafficking of AMPA subtype glutamate receptors (AMPARs) from intracellular compartments to synapses is thought to be a major mechanism underlying the expression of long-term potentiation (LTP), a cellular substrate for learning and memory. However, it remains unclear whether the AMPAR trafficking that takes place during LTP is due to a targeted insertion of AMPARs directly into the synapse or delivery to extrasynaptic sites followed by translocation into the synapse. Here, we provide direct physiological evidence that LTP induced by a theta-burst pairing and tetanic stimulation protocols causes the rapid delivery of AMPARs to a perisynaptic site. Perisynaptic AMPARs do not normally detect synaptically released glutamate but can do so when the glial glutamate transporter EAAT1 is inhibited. AMPARs can be detected at this perisynaptic site before, but not after, the full expression of LTP. The appearance of perisynaptic AMPARs requires postsynaptic exocytosis, PKA signaling, and the C-terminal region of GluR1 subunit of AMPARs but not actin polymerization. Actin polymerization after LTP induction is required to retain AMPARs at the perisynaptic site after their appearance. Low-frequency stimulation given shortly after LTP induction leads to activity-dependent removal of perisynaptic AMPARs and suppresses the subsequent expression of LTP. These results demonstrate that AMPARs are rapidly trafficked to perisynaptic sites shortly after LTP induction and suggest that the delivery and maintenance of perisynaptic AMPARs may serve as a checkpoint in the expression of LTP.actin ͉ dendritic spine ͉ trafficking ͉ TBOA ͉ two-photon imaging A ctivity-induced modification of neuronal connections is essential for the development of the nervous system and may underlie some forms of learning and memory. One widely examined form of synaptic plasticity is long-term potentiation (LTP). LTP leads to the synaptic insertion of glutamate receptors of the AMPA subtype (AMPARs) (1-4). Recent studies also suggest that this synaptic incorporation of AMPARs may stabilize spine modifications associated with LTP (5, 6). Postsynaptic exocytosis (7,8), PKA activity (9), and AMPARs containing the GluR1 subunit (10) are implicated in the synaptic incorporation of AMPARs during LTP, but it remains unclear whether LTP leads to the direct insertion of AMPARs at the postsynaptic density (PSD) or to insertion at extrasynaptic regions followed by translocation into the PSD.Consistent with the latter idea, AMPAR targeting from intracellular compartments to the cell surface can occur via mechanisms that are distinct from AMPAR targeting from the cell surface to the synapse (11). By visualizing the movement of transfected AMPAR subunits or specific domains of AMPAR subunits in culture, trafficking of AMPARs can be observed in response to LTP induced by synaptic activity or chemical induction protocols. Using this approach, studies have found that AMPARs containing GluR1 can be inserted into the plasma membrane from intracellular stores (2). Lateral mobili...

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Section: Resultsmentioning

confidence: 99%

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

Yang

Wang

Frerking

et al. 2008

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

132

126

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“…These data might help to explain the critical role of NF-B in behavior and synaptic plasticity, in particular L-LTP, revealed by our mouse model. PKA and CREB have been proposed as critical regulators of long-term memory and L-LTP (4,12,38,49,53). Recently, the view of CREB as a pivotal component in mouse hippocampal synaptic plasticity and learning has been questioned, since mice with deletion of all CREB isoforms in neurons present normal hippocampal LTP, LTD, and long-term memory (3).…”

Section: Discussionmentioning

confidence: 99%

“…However, hypomorphic transdominant negative KCREB mutants, which do not show effects in electrically induced LTP, are deficient in cAMP-mediated long-lasting potentiation (49). It has also been shown that postsynaptic application of a peptide inhibitor of PKA blocks long-lasting potentiation in hippocampal neurons (12); conversely, a constitutively active form of PKAcat␣ expressed into CA1 pyramidal neurons leads to long-lasting facilitation (4,12). Altogether, these data indicate that PKAcat␣ is involved in the long-lasting forms of synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

NF-κB Regulates Spatial Memory Formation and Synaptic Plasticity through Protein Kinase A/CREB Signaling

Kaltschmidt

Ndiaye

Körte

et al. 2006

Molecular and Cellular Biology

189

163

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Synaptic activity-dependent de novo gene transcription is crucial for long-lasting neuronal plasticity and long-term memory. In a forebrain neuronal conditional NF-κB-deficient mouse model, we demonstrate here that the transcription factor NF-κB regulates spatial memory formation, synaptic transmission, and plasticity. Gene profiling experiments and analysis of regulatory regions identified the α catalytic subunit of protein kinase A (PKA), an essential memory regulator, as a new NF-κB target gene. Consequently, NF-κB inhibition led to a decrease in forskolin-induced CREB phosphorylation. Collectively, these results disclose a novel hierarchical transcriptional network involving NF-κB, PKA, and CREB that leads to concerted nuclear transduction of synaptic signals in neurons, accounting for the critical function of NF-κB in learning and memory.

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“…In contrast, the site of PKA action for L-LTP at CA3-CA1 synapses has been less well defined but has been presumed to be, at least in part, postsynaptic because of the requirement for transcription (13). Moreover, Duffy and Nguyen (23) found that PKA activation in the CA1 neuron is necessary and sufficient to induce L-LTP at Schaffer collateral synapses, although a role for presynaptic PKA was not directly addressed. Based on our finding that RIM1␣, a prominent PKA substrate, is required for L-LTP, we suggest that this form of plasticity is likely to also have a presynaptic requirement for PKA activation in addition to any postsynaptic role for this enzyme.…”

Section: Discussionmentioning

confidence: 99%

Genetic evidence for a protein-kinase-A-mediated presynaptic component in NMDA-receptor-dependent forms of long-term synaptic potentiation

Huang

Zakharenko

Schoch

et al. 2005

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

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T he molecular analysis of long-term plasticity in the mammalian brain has to confront the existence of multiple forms of plasticity, both at a single synapse and across distinct synapses (1). Thus, whereas long-term potentiation (LTP) in its early phase (E-LTP) at the Schaffer collateral synapses between hippocampal CA3 and CA1 pyramidal neurons depends on postsynaptic NMDA receptor (NMDAR) activation and is independent of protein kinase A (PKA), LTP at hippocampal mossy-fiber synapses and cerebellar parallel-fiber synapses requires presynaptic PKA activation but not postsynaptic activation of NMDARs (2, 3). Moreover, whereas expression of Schaffer collateral E-LTP has a prominent postsynaptic component, both mossy-fiber and parallel-fiber LTP are expressed presynaptically. These distinctions have been confirmed at the molecular level. Although the presynaptic vesicle proteins Rab3A, a small GTP-binding protein, and its effector, RIM1␣, are required for both mossy-fiber and parallel-fiber LTP, they are not necessary for NMDAR-dependent, Schaffer collateral LTP (4-7). These results suggest that NMDAR-dependent͞PKA-independent LTP and NMDAR-independent͞PKA-dependent LTP may constitute discrete cellular modules that are differentially expressed at different synapses. Here we investigate whether these modules can be combined to yield more complex forms of synaptic plasticity.We address this question by examining whether Rab3A and RIM1␣ can also participate in forms of LTP that require both PKA and NMDA receptors and that have a presynaptic component to their expression. Rab3A and RIM1␣ are attractive targets for long-term PKA-dependent presynaptic plasticity because they both act to regulate the efficiency of transmitter release (7,8), and RIM1␣ (but not Rab3A) is phosphorylated by PKA (9). Thus, we were interested in knowing whether Rab3A͞RIM constitutes a module that is generally required for PKA-mediated forms of presynaptic long-term plasticity or is required for only those forms of plasticity that do not recruit NMDAR-dependent postsynaptic induction mechanisms.Here, we examined knockout mice deficient in Rab3A or RIM1␣ to study the role of these proteins in the induction of corticoamygdala LTP and late LTP (L-LTP) at CA3-CA1 hippocampal synapses, two forms of PKA-mediated long-term presynaptic plasticity that require NMDAR-dependent postsynaptic Ca 2ϩ influx (10-14). Our results show that Rab3A is required for the expression of both corticoamygdala LTP and CA3-CA1 L-LTP; RIM1␣ is also required for CA3-CA1 L-LTP. These results demonstrate a surprising unity in the molecular pathway that mediates four forms of PKA-dependent presynaptic plasticity at four distinct types of synapses in the mammalian brain. Materials and MethodsThe generation of the Rab3A and RIM1␣ mutant mouse lines (6, 8) and mouse breeding and care (15, 16) have been described previously. All analyses were carried out with homozygous wild-type and mutant littermates from matings of heterozygotes.Transverse slices (400 m) were prepared from eith...

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Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

Cited by 64 publications

References 66 publications

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

Delivery of AMPA receptors to perisynaptic sites precedes the full expression of long-term potentiation

NF-κB Regulates Spatial Memory Formation and Synaptic Plasticity through Protein Kinase A/CREB Signaling

Genetic evidence for a protein-kinase-A-mediated presynaptic component in NMDA-receptor-dependent forms of long-term synaptic potentiation

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