Different Rho GTPase–dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation

Rex, Christopher S.; Chen, Lulu Y.; Sharma, Anupam; Liu, Jihua; Babayan, Alex H.; Gall, Christine M.; Lynch, Gary

doi:10.1083/jcb.200901084

Cited by 273 publications

(360 citation statements)

References 54 publications

(82 reference statements)

Supporting

Mentioning

338

Contrasting

Order By: Relevance

“…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%

Synaptic evidence for the efficacy of spaced learning

Kramár¹,

Babayan²,

Gavin

et al. 2012

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

Self Cite

157

189

View full text Add to dashboard Cite

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...

show abstract

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.

Self Cite

157

189

View full text Add to dashboard Cite

show abstract

“…One important caveat to note, however, is that total inhibition of Rho-GTPases might, in fact, not be an optimal strategy. 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].…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Actin is abundant in presynaptic terminals and postsynaptic spines (11), and numerous studies highlight the relevance of actin dynamics for postsynaptic plasticity (12). Pharmacologic studies and the subsynaptic distribution of actin filaments also suggest a role for actin in neurotransmitter release (13,14).…”

mentioning

confidence: 99%

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Zimmermann

Jene

Wolf

et al. 2015

Biological Psychiatry

View full text Add to dashboard Cite

BACKGROUND: Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential for actin dynamics, which is critical for synaptic function. Two ADF/cofilin family members, ADF and n-cofilin, are highly abundant in the brain, where they are present in excitatory synapses. Previous studies demonstrated the relevance of n-cofilin for postsynaptic plasticity, associative learning, and anxiety. These studies also suggested overlapping functions for ADF and n-cofilin. METHODS: We performed pharmacobehavioral, electrophysiologic, and electron microscopic studies on ADF and n-cofilin single mutants and double mutants (named ACC mice) to characterize the importance of ADF/cofilin activity for synapse physiology and mouse behavior. RESULTS: The ACC mice, but not single mutants, exhibited hyperlocomotion, impulsivity, and impaired working memory. Hyperlocomotion and impulsive behavior were reversed by methylphenidate, a psychostimulant commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Also, ACC mice displayed a disturbed morphology of striatal excitatory synapses, accompanied by strongly increased glutamate release. Blockade of dopamine or glutamate transmission resulted in normal locomotion. CONCLUSIONS: Our study reveals that ADHD can result from a disturbed balance between excitation and inhibition in striatal circuits, providing novel insights into the mechanisms underlying this neurobehavioral disorder. Our results link actin dynamics to ADHD, suggesting that mutations in actin regulatory proteins may contribute to the etiology of ADHD in humans.

show abstract

Different Rho GTPase–dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation

Cited by 273 publications

References 54 publications

Synaptic evidence for the efficacy of spaced learning

Synaptic evidence for the efficacy of spaced learning

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

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Contact Info

Product

Resources

About