Opposing actions of protein kinase A and C mediate Hebbian synaptic plasticity

Li, Minxu; Jia, Min; Jiang, Hao; Dunlap, Veronica; Nelson, Phillip G.

doi:10.1038/nn0901-871

Cited by 31 publications

(46 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, when one input to myotubes innervated by each of the two populations of motoneurons in our tissue culture system was stimulated, the stimulated input showed a significant but relatively small decrease (Fig. 3, Wild Stim Side), whereas the other, nonstimulated synapse was diminished by Ͼ50% (significantly more than the stimulated input) (Li et al, 2001a) (Fig. 3, Wild Unstim Side).…”

Section: Pkc Theta Is Required For Heterosynaptic Activity-dependent mentioning

confidence: 88%

“…Serine protein kinases [both protein kinase A (PKA) and PKC] play a role in the use-dependent synapse modification, with PKC activation resulting in a decrease in synaptic strength, whereas PKA action opposes or reverses the PKC effect (Li et al, 2001a(Li et al, , 2002. The involvement of PKC in the synapse elimination process was also observed in vivo but was seen only during the first two-thirds of the 2-3 week postnatal period during which synapse elimination occurs in vivo (Lanuza et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of the Theta Isoform of Protein Kinase C (PKC) in Activity-Dependent Synapse Elimination: Evidence from the PKC Theta Knock-Out MouseIn VivoandIn Vitro

Jia²,

Yang³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

PKC plays a critical role in competitive activity-dependent synapse modification at the neuromuscular synapse in vitro and in vivo. This action involves a reduction of the strength of inactive inputs to muscle cells that are activated by other inputs. A decrease of postsynaptic responsiveness and a loss of postsynaptic acetyl choline receptors account for the heterosynaptic loss in vitro. The loss is not seen in preparations in which PKC has been blocked pharmacologically. Here, we show that the loss does not occur in in vitro preparations made from animals genetically modified to lack the theta isoform of PKC. Synapse elimination in the newborn period in vivo is delayed but is eventually expressed in knock-out animals. PKC-dependent synapse reduction is suppressed in heterologous cultures combining normal nerve and PKC theta-deficient muscle, as might be expected from the postsynaptic locus of the changes that underlie the activitydependent plasticity. Preparations in which PKC theta-deficient neurons innervated normal muscle also exhibited a marked deficit in PKC-deficient synapse reduction. The presynaptic action of PKC theta implied by this observation is blocked by TTX, and we propose that activity-related synapse strengthening is decreased by presynaptic PKC theta. Thus, PKC theta in both presynaptic and postsynaptic elements plays a critical role in activity-dependent synapse modulation and loss. We provide a model for activity-dependent synapse loss incorporating these findings.

show abstract

Section: Pkc Theta Is Required For Heterosynaptic Activity-dependent mentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

The Role of the Theta Isoform of Protein Kinase C (PKC) in Activity-Dependent Synapse Elimination: Evidence from the PKC Theta Knock-Out MouseIn VivoandIn Vitro

Jia²,

Yang³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Notably, stimulation of cAMP synthesis rescued AChR lifetime in denervated (12,19) and dystrophic muscles (14). Several groups have described antagonistic functions of protein kinase C and PKA on AChR persistence and synaptic strength (18,20,21): although activation of protein kinase C destabilizes AChRs, PKA activity protects this receptor from such destabilization (18). In this context, the neuropeptide and cAMP agonist, α-calcitonin gene-related peptide (CGRP), is thought to be a prime regulator of PKA activation (18,20).…”

mentioning

confidence: 99%

“…Several groups have described antagonistic functions of protein kinase C and PKA on AChR persistence and synaptic strength (18,20,21): although activation of protein kinase C destabilizes AChRs, PKA activity protects this receptor from such destabilization (18). In this context, the neuropeptide and cAMP agonist, α-calcitonin gene-related peptide (CGRP), is thought to be a prime regulator of PKA activation (18,20). CGRP is present in motor nerve terminals and is released in an activity-dependent manner (22).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Röder¹,

Choi²,

Reischl

et al. 2010

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

108

View full text Add to dashboard Cite

Myosin V motor proteins facilitate recycling of synaptic receptors, including AMPA and acetylcholine receptors, in central and peripheral synapses, respectively. To shed light on the regulation of receptor recycling, we employed in vivo imaging of mouse neuromuscular synapses. We found that myosin Va cooperates with PKA on the postsynapse to maintain size and integrity of the synapse; this cooperation also regulated the lifetime of acetylcholine receptors. Myosin Va and PKA colocalized in subsynaptic enrichments. These accumulations were crucial for synaptic integrity and proper cAMP signaling, and were dependent on AKAP function, myosin Va, and an intact actin cytoskeleton. The neuropeptide and cAMP agonist, calcitonin-gene related peptide, rescued fragmentation of synapses upon denervation. We hypothesize that neuronal ligands trigger local activation of PKA, which in turn controls synaptic integrity and turnover of receptors. To this end, myosin Va mediates correct positioning of PKA in a postsynaptic microdomain, presumably by tethering PKA to the actin cytoskeleton.cAMP | muscle | neuromuscular junction | microdomain | synaptic plasticity R ecently, myosin V motor proteins were found to be crucial for the plasticity of central and peripheral synapses by facilitating, respectively, the recycling of AMPA (1-3) and acetylcholine receptors (AChRs) (4). The neuromuscular junction (NMJ) is the synapse between motor neurons and skeletal muscle fibers. Even though it is formed during ontogenesis and then maintained over the years (5), half-lives (t 1/2 ) of a few days are typical for its protein constituents, such as the AChR (6). The high enrichment of AChRs in the postsynapse is regulated by accurate targeting and turnover of this receptor. Vesicular transport is employed for this purpose, using different routes of exocytosis, endocytosis, and recycling (7-9). We identified myosin Va as the first motor protein involved in AChR trafficking and have found it to facilitate its recycling (4). Down-regulation of myosin Va led to a reduced t 1/2 of AChRs (4) similar to pathological conditions, such as denervation (6, 10-13) or dystrophy (14). A shortened t 1/2 of AChRs accompanies morphological changes of the NMJ: while NMJs in mouse muscles are normally elliptic and pretzel-shaped (15), they elongate and fragment under pathological conditions (16,17).Previous studies have revealed a major role of cAMP signaling in controlling the t 1/2 of AChRs (12, 18). cAMP is formed upon activation of G protein-coupled receptors and mediates its effects mainly through protein kinase A (PKA). Notably, stimulation of cAMP synthesis rescued AChR lifetime in denervated (12,19) and dystrophic muscles (14). Several groups have described antagonistic functions of protein kinase C and PKA on AChR persistence and synaptic strength (18,20,21): although activation of protein kinase C destabilizes AChRs, PKA activity protects this receptor from such destabilization (18). In this context, the neuropeptide and cAMP agonist, α-calcitonin gene-rel...

show abstract

Extracellular ATP in activity‐dependent remodeling of the neuromuscular junction

Jia

Fields

et al. 2007

Developmental Neurobiology

Self Cite

View full text Add to dashboard Cite

Electrical activity during early development affects the development and maintenance of synapses (Spitzer [2006]: Nature 4447:707-712), but the intercellular signals regulating maintenance of synapses are not well identified. At the neuromuscular junction, adenosine 5-triphosphate (ATP) is coreleased with acetylcholine at activated nerve terminals to modulate synaptic function. Here we use cocultured mouse motor neurons and muscle cells in a three-compartment cell culture chamber to test whether endogenously released ATP plays a role in activity-dependent maintenance of neuromuscular synapses. The results suggest that ATP release at the synapse counters the negative effect of electrical activity, thus stabilizing activated synapses. Confirming our previous work (Li et al. [2001]: Nat Neurosci 4:871-872), we found that in doubly innervated muscles, electrical stimulation induced heterosynaptic downregulation of the nonstimulated convergent input to the muscle fiber with no or little change of the stimulated inputs. However, in preparations that were stimulated in the presence of apyrase, an enzyme that degrades extracellular ATP, synapse downregulation of stimulated inputs was substantial and significant, and end plate potentials were reduced. Apyrase treatment for 20 h in the absence of stimulation did result in moderate diminution, but this was prevented by blocking spontaneous neural activity with tetrodotoxin. The P2 receptor blocker, suramin, also induced activity-dependent synapse diminution. The decrease in synaptic efficacy produced by prolonged stimulation in the presence of apyrase persisted for greater than 20 h, consistent with a developmental time-course and distinct from the rapid neuromodulatory actions of ATP that have been demonstrated by others. We conclude that extracellular ATP promotes stabilization of the neuromuscular junction and may play a role in activity-dependent synaptic modification during development.

show abstract

Opposing actions of protein kinase A and C mediate Hebbian synaptic plasticity

Cited by 31 publications

References 11 publications

The Role of the Theta Isoform of Protein Kinase C (PKC) in Activity-Dependent Synapse Elimination: Evidence from the PKC Theta Knock-Out MouseIn VivoandIn Vitro

The Role of the Theta Isoform of Protein Kinase C (PKC) in Activity-Dependent Synapse Elimination: Evidence from the PKC Theta Knock-Out MouseIn VivoandIn Vitro

Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Extracellular ATP in activity‐dependent remodeling of the neuromuscular junction

Contact Info

Product

Resources

About