Local, persistent activation of Rho GTPases during plasticity of single dendritic spines

Murakoshi, Hideji; Wang, Hong; Yasuda, Ryohei

doi:10.1038/nature09823

Cited by 496 publications

(609 citation statements)

References 42 publications

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“…Recent studies have shown that induction of plasticity at a single spine transiently lowers the plasticity threshold at adjacent spines (20). The mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics (24)(25)(26). Therefore, we asked if TBS2 induces F-actin polymerization in spines neighboring the synapses potentiated by TBS1.…”

Section: Resultsmentioning

confidence: 99%

“…Uncaging glutamate near the tip of a single dendritic spine [single spine glutamate uncaging (SSGU)] results in a coordinated increase in spine volume and enhanced synaptic function lasting for more than an hour (20,21). This form of plasticity shares many properties with Schaffer collateral LTP, including dependence on N-methyl-D-aspartate receptors (NMDARs), Rho GTPase signaling, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) phosphorylation, F-actin polymerization and synaptic AMPAR insertion (20)(21)(22)(23)(24). Uncaging glutamate near small spines in young and adult slices caused an increase in head volume that remained elevated above baseline levels for at least 45 min (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Synaptic evidence for the efficacy of spaced learning

Kramár¹,

Babayan²,

Gavin

et al. 2012

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

142

189

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The superiority of spaced vs. massed training is a fundamental feature of learning. Here, we describe unanticipated timing rules for the production of long-term potentiation (LTP) in adult rat hippocampal slices that can account for one temporal segment of the spaced trials phenomenon. Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used. Analyses of Factin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were "missed" by the first stimulation bout. Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions, suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections. We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced. Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.A n extensive body of experimental work indicates that periodic exposure to the same material results in better retention than a single "cramming" session. Although this distributed practice effect was first recognized in late 19th century (1-3), and has since been the subject of a very large psychological literature (4), the neurobiological processes that give rise to the phenomenon are poorly understood. Activity-dependent synaptic plasticity, and, in particular, long-term potentiation (LTP) of glutamatergic transmission, is thought to underlie rapid storage of new information (5, 6). Therefore, it is surprising that little experimental attention has been given to the possibility that specialized features of LTP may contribute to the spaced trials (distributed practice) effect. This likely reflects the lack of data indicating that the substrates of the potentiation effect include properties that are engaged, or enhanced, only by widely spaced stimulation episodes. Specifically, several types of studies point to the conclusion that the elaborate processes yielding fully developed LTP reach completion within 10-15 min (5, 7, 8); these findings do not include results suggestive of a delayed capacity for triggering additional changes to already potentiated synapses. There is considerable evidence for a later LTP stabilization step involving protein synthesis (9), but the effects of this on subsequent plasticity involve inputs other than those already expressing potentiation (10).Here, we describe a set of mechanisms and timing rules in hippocampus that result in widely spaced episodes of theta burst stimulation (TBS) generating a much greater degree of LT...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synaptic evidence for the efficacy of spaced learning

Kramár¹,

Babayan²,

Gavin

et al. 2012

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

142

189

View full text Add to dashboard Cite

show abstract

“…11 The specific link between increased concentration of intracellular calcium ions and RhoA activation in scattering epithelial cells is likely multifaceted. Just as CaMKII links calcium fluxes to RhoA activation in the dendritic spine, 94 CaMKII might link calcium fluxes to RhoA activation and then global myosin-based contractility in scattering epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Rho-mediated activation of cofilin occurs downstream of calcium fluxes in dendritic spines is calcium-dependent. 94 Interestingly, it is calcium-mediated activation of CaMKII that in turn drives longer term RhoA activation in this sytem; a CaMKII inhibitor blocks RhoA-ROCK pathway activation. 94 Though this data suggests CaMKII could be the key mediator between calcium influxes and RhoAmediated cellular contractility during epithelial scattering, the molecular mechanism by which CaMKII stimulates RhoA activation remains unidentified.…”

Section: Molecular Regulation Of Epithelial Scattering By Calcium/calmentioning

confidence: 99%

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

2016

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Epithelial tissues use adherens junctions to maintain tight interactions and coordinate cellular activities. Adherens junctions are remodeled during epithelial morphogenesis, including instances of epithelialmesenchymal transition, or EMT, wherein individual cells detach from the tissue and migrate as individual cells. EMT has been recapitulated by growth factor induction of epithelial scattering in cell culture. In culture systems, cells undergo a highly reproducible series of cell morphology changes, most notably cell spreading followed by cellular compaction and cell migration. These morphology changes are accompanied by striking actin rearrangements. The current evidence suggests that global changes in actomyosin-based cellular contractility, first a loss of contractility during spreading and its activation during cell compaction, are the main drivers of epithelial scattering. In this review, we focus on how spreading and contractility might be controlled during epithelial scattering. While we propose a central role for RhoA, which is well known to control cellular contractility in multiple systems and whose role in epithelial scattering is well accepted, we suggest potential roles for additional cellular systems whose role in epithelial cell biology has been less well documented. In particular, we propose critical roles for vesicle recycling, calcium channels, and calcium-dependent kinases.

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“…Rho-GTPases play important physiological roles in normal synaptic functions, and their activities are essential for learning and memory, and for the establishment of LTP [48]. As a result, total inhibition may interfere with longterm signaling required for spine structural plasticity [49]. An alternative approach may be to manipulate selectively the activity of the regulators of Rho-GTPase signaling.…”

Section: Direct Modulation Of Rho-gtpases For Ad Treatmentmentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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Local, persistent activation of Rho GTPases during plasticity of single dendritic spines

Cited by 496 publications

References 42 publications

Synaptic evidence for the efficacy of spaced learning

Synaptic evidence for the efficacy of spaced learning

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

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