Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice

Cao, Guojie; Harris, Kristen M.

doi:10.1152/jn.00297.2014

Cited by 33 publications

(50 citation statements)

References 59 publications

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“…At P15, the next bout could stabilize the new connectivity, while in adults the next bout could recruit vesicles to new docking sites at the enlarged nascent zones. This interpretation is consistent with recent findings showing that sufficient time must pass before the initial LTP became unsaturated and a second bout of TBS could augment the potentiation (Babayan et al, 2012; Bell et al, 2014; Cao and Harris, 2014). …”

Section: Discussionsupporting

confidence: 93%

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

Smith

Bourne

Cao

et al. 2016

eLife

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113

120

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Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation. At 30 and 120 min after TBS-LTP, vesicles were decreased only in presynaptic boutons that contained mitochondria at P15, and vesicle decrement was greatest in adult boutons containing mitochondria. Presynaptic mitochondrial cristae were widened, suggesting a sustained energy demand. Thus, mitochondrial proximity reflected enhanced vesicle mobilization well after potentiation reached asymptote, in parallel with the apparently silent addition of new dendritic spines at P15 or the silent enlargement of synapses in adults.DOI: http://dx.doi.org/10.7554/eLife.15275.001

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Section: Discussionsupporting

confidence: 93%

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

Smith

Bourne

Cao

et al. 2016

eLife

Self Cite

113

120

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“…The studies also demonstrate that the facilitating effects of spacing, for both genotypes, align with the periodicity of afferent stimulation required to enhance hippocampal LTP (10,17). This results in a narrow time window for augmenting learning: Spaced trials were effective with a minimum of three trials spaced by 60 min while 20-or 120-min intervals did not improve retention scores.…”

Section: Discussionmentioning

confidence: 68%

“…We gave additional mice 5-min training daily for 6 d: OLM was still absent in the KOs indicating that they do not form a partial memory trace after 5 min of training. We focused on OLM because its retrieval depends on hippocampal field CA1 (11,14), which exhibits an elevated LTP threshold in Fmr1 KOs (7,8) and enhanced potentiation with spaced stimulation in WTs (10,17). However, Fmr1 KOs have more robust LTP impairments in other regions including cortex (6,(18)(19)(20)(21).…”

Section: Significancementioning

confidence: 99%

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

Seese

Wang

Yao

et al. 2014

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

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Recent studies have shown that short, spaced trains of afferent stimulation produce much greater long-term potentiation (LTP) than that obtained with a single, prolonged stimulation episode. The present studies demonstrate that spaced training regimens, based on these LTP timing rules, facilitate learning in wild-type (WT) mice and can offset learning and synaptic signaling impairments in the fragile X mental retardation 1 (Fmr1) knockout (KO) model of fragile X syndrome. We determined that 5 min of continuous training supports object location memory (OLM) in WT but not Fmr1 KO mice. However, the same amount of training distributed across three short trials, spaced by one hour, produced robust long-term memory in the KOs. At least three training trials were needed to realize the benefit of spacing, and intertrial intervals shorter or longer than 60 min were ineffective. Multiple short training trials also rescued novel object recognition in Fmr1 KOs. The spacing effect was surprisingly potent: just 1 min of OLM training, distributed across three trials, supported robust memory in both genotypes. Spacing also rescued training-induced activation of synaptic ERK1/2 in dorsal hippocampus of Fmr1 KO mice. These results show that a spaced training regimen designed to maximize synaptic potentiation facilitates recognition memory in WT mice and can offset synaptic signaling and memory impairments in a model of congenital intellectual disability.Fmr1 KO | hippocampus | object location memory | massed training | novel object recognition F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) (1). Currently no treatments exist for cognitive deficits associated with FXS or other neurodevelopmental disorders with ID. Research on the fragile X mental retardation 1 (Fmr1) KO mouse model of FXS has identified impairments in synaptic signaling required to produce lasting synaptic modifications (2-6) with corresponding disturbances in the activation threshold and stabilization of hippocampal long-term potentiation (LTP) (7,8). These findings suggest specific synaptic disturbances underlie learning problems in FXS as well as targets for therapeutic interventions to improve cognitive function.The present experiments tested predictions from LTP studies as to how modified training paradigms might rescue synaptic signaling and learning in Fmr1 KO mice. There is a deep literature demonstrating that individuals learn better when trained in short trials spaced in time than in a single, extended training episode (9). We recently found that LTP exhibits a synaptic analog for this "spaced trials effect" (10). Specifically, in hippocampal field CA1 short trains of theta burst afferent stimulation spaced by 60 min elicit far greater synaptic potentiation than can be achieved with long theta trains or by repeated trains applied at shorter intervals. As LTP is considered a mechanism of memory encoding, we propose that spaced training regimens that use the same 60-min periodicity should facilitate hippocampus...

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“…The required refractory period of ~1 hour between successive theta-burst stimuli to induce progressive increments in hippocampal LTP 46,47 may be in line with the first of these variants, which is that short intervals are insufficient for consolidation and consequent summation of memory traces. The refractory period appears to be necessary to complete the priming of dendritic spines that were stimulated, but not potentiated, by the first theta-burst stimulus.…”

Section: Recent Data and Learning Theoriesmentioning

confidence: 77%

“…Thus, studying the differential dynamics of dendritic spine remodelling following massed versus spaced stimuli is likely to provide insight into processes underlying the effectiveness of spaced training. Studies using rat hippocampal slices found that LTP induced by multiple trains of theta-burst stimuli was accompanied by extensive remodelling of synaptic ultrastructures 44,45 and that subsequent spaced trains of theta-burst stimuli, with intervals of 60 minutes or more between the trains, were needed for optimal reinforcement of LTP 46 . Stimulated dendritic spines were remodelled over a period of more than 1 hour, leading to enlargement of the existing functional postsynaptic density 45 and the presynaptic active zone 44 .…”

Section: Molecular Traces Of Timementioning

confidence: 99%

The right time to learn: mechanisms and optimization of spaced learning

2016

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For many types of learning, spaced training, which involves repeated long inter-trial intervals, leads to more robust memory formation than does massed training, which involves short or no intervals. Several cognitive theories have been proposed to explain this superiority, but only recently have data begun to delineate the underlying cellular and molecular mechanisms of spaced training, and we review these theories and data here. Computational models of the implicated signalling cascades have predicted that spaced training with irregular inter-trial intervals can enhance learning. This strategy of using models to predict optimal spaced training protocols, combined with pharmacotherapy, suggests novel ways to rescue impaired synaptic plasticity and learning.

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Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice

Cited by 33 publications

References 59 publications

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice

The right time to learn: mechanisms and optimization of spaced learning

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