Elsevier

Neuropharmacology

Volume 64, January 2013, Pages 27-36
Neuropharmacology

Invited review
Differences between synaptic plasticity thresholds result in new timing rules for maximizing long-term potentiation

https://doi.org/10.1016/j.neuropharm.2012.07.006Get rights and content

Abstract

The fundamental observation that the temporal spacing of learning episodes plays a critical role in the efficiency of memory encoding has had little effect on either research on long-term potentiation (LTP) or efforts to develop cognitive enhancers. Here we review recent findings describing a spaced trials phenomenon for LTP that appears to be related to recent evidence that plasticity thresholds differ between synapses in the adult hippocampus. Results of tests with one memory enhancing drug suggest that the compound potently facilitates LTP via effects on ‘high threshold’ synapses and thus alters the temporally extended timing rules. Possible implications of these results for our understanding of LTP substrates, neurobiological contributors to the distributed practice effect, and the consequences of memory enhancement are discussed.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Highlights

► New LTP timing rules are identified for adult hippocampus. ► A post-TBS refractory period for synaptic signaling and LTP induction is identified. ► There are synapses with high and low threshold for LTP induction in adult hippocampus. ► We propose spine crosstalk primes high threshold synapses for later potentiation. ► Ampakine treatment facilitates potentiation of high threshold synapses.

Introduction

It is well established that short bursts of afferent stimulation are more effective at inducing LTP when separated by the period of the theta rhythm (∼200 ms) than when delivered at other intervals (Larson et al., 1986). This observation, in addition to providing a physiologically relevant and stereotyped means for generating synaptic modifications in adult forebrain, linked LTP to activity patterns occurring during learning (Otto et al., 1991; Buzsaki, 2005) and thus indirectly to memory encoding (Vertes, 2005; Axmacher et al., 2006). Subsequent work identified the mechanisms responsible for the peculiar efficiency of theta burst stimulation (TBS) and showed that the pattern is also highly effective in studies using transcranial magnetic stimulation of human cortex (Teo et al., 2011). Given these points, it is surprising that the types of parametric studies used to develop the TBS paradigm have not been repeated using periodic delivery of theta patterns across much longer time frames. This is all the more so in light of the improved memory encoding obtained by spacing learning trials (Wickelgren, 1974; Braun and Rubin, 1998; Cepeda et al., 2006; Benjamin and Tullis, 2010), that are each likely associated with cue-initiated theta activity, by hours or days. By itself, the ubiquitous spaced trials effect found in behavioral studies raises the expectation that widely separated theta trains will affect LTP in ways not found with more closely spaced applications.

The present paper surveys recent studies that confirmed the above prediction and describe candidate mechanisms that would allow theta trains separated by long intervals to greatly enhance the magnitude of LTP. Specifically, the LTP version of the spaced trials effect appears to involve recruitment into the potentiated state of synapses with initially very high plasticity thresholds. These results, along with analyses using single spine glutamate uncaging, show that the majority of synaptic contacts in adult hippocampus are not modified by a single train of theta burst stimulation but are in some manner primed by the theta train so as to become responsive to a second bout of theta delivered after a long delay. Possible explanations for this unexpected temporal requirement for capturing synapses ‘missed’ by a single TBS episode will be discussed in some detail. We will also summarize the first experiments asking if a memory enhancing compound interacts with the newly identified LTP timing rules. The results raise new questions about the meaning of cognitive enhancement.

Section snippets

Rules for producing maximal LTP

Early work relating theta to LTP suggested that a single 10 burst TBS train produced a near maximal degree of potentiation. Shortening the train reduced the percent LTP while extending it yielded no further enhancement of synaptic responses (Larson et al., 1986). Moreover, the potentiation induced by TBS was found to be remarkably stable, showing no evidence of delayed changes over extended periods of recording. Chronic recording studies first established this point (Staubli and Lynch, 1987;

LTP2 involves potentiation of synapses ‘missed‘ by TBS1

The existence of LTP2 could indicate that individual synapses have multiple potentiation steps or that TBS1 fails to modify all of the contacts formed by the axons stimulated by TBS1. The literature is unclear with regard to these ideas. However, recent advances in the analysis of the cell biological underpinnings of LTP describe methods that could in principle be used to test if TBS2 triggers events associated with enduring potentiation at synapses other than those engaged by TBS1. Those

A test of the hypothesis that adult hippocampus contains spines with different plasticity thresholds

A now sizable body of studies first using electron microscopy and then live imaging or immunostaining indicates that LTP is associated with substantial changes to spine and synapse morphology (Chen et al., 2007; Fortin et al., 2010; Gu et al., 2010; Wang and Zhou, 2010; Bosch and Hayashi, 2011). Previous studies have also shown that local single spine glutamate uncaging (SSGU) can elicit coordinated and enduring increases in spine head volume and increases in synaptic function (Matsuzaki

Mechanisms underlying the delayed reduction of plasticity thresholds

The most straightforward interpretation of the results obtained with the TBS1/TBS2 paradigm is that a single train of theta bursts i) induces LTP in low threshold synapses and ii) ‘primes’ high threshold connections to respond to the delayed arrival of a second theta train. What type of mechanism might account for the latter effect? Uncaging studies using immature neurons have uncovered evidence for spine crosstalk involving the diffusion of material from stimulated spines to neighbors located

A memory enhancing drug modifies LTP timing rules

As noted, drugs that positively modulate AMPA receptors, and thereby increase the size of fast EPSCs (‘ampakines’), both lower the threshold and raise the ceiling for LTP (Staubli et al., 1994; Arai and Kessler, 2007). Ampakines also improve retention scores in diverse learning paradigms using rodents, rabbits, and primates (e.g., Staubli et al., 1994a; Shors et al., 1995; Porrino et al., 2005; Hampson et al., 2009). A likely explanation for these effects is that the compounds markedly increase

Discussion

Three lines of evidence described here lead to the conclusion that the threshold for inducing stable LTP differs between synapses in the adult hippocampus. First, TBS2 increases the number of spines containing high concentrations of polymerized actin to values that are substantially greater than those found after stimulation of the same fibers with TBS1. Second, live spine imaging has shown that while many spines in adult hippocampus undergo LTP-related morphological changes in response to

Acknowledgements

This research was supported, in part, by NINDS grants NS045260 (G.L., C.M.G.) and NS064079 (G.R.), NIMH grant MH083346 (C.G.), and ONR MURI grant N00014-10-1-0072 (G.L.).

References (81)

  • A. Huttenlocher et al.

    Regulation of cell migration by the calcium-dependent protease calpain

    J. Biol. Chem.

    (1997)
  • T. Kleindienst et al.

    Activity-dependent clustering of functional synaptic inputs on developing hippocampal dendrites

    Neuron

    (2011)
  • E.A. Kramár et al.

    Developmental and regional differences in the consolidation of long-term potentiation

    Neuroscience

    (2003)
  • R. Lamprecht et al.

    Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala

    Neuroscience

    (2006)
  • J. Larson et al.

    Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal theta-rhythm

    Brain Res.

    (1988)
  • J. Larson et al.

    Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation

    Brain Res.

    (1986)
  • G. Lynch et al.

    The substrates of memory: defects, treatments, and enhancement

    Eur. J. Pharmacol.

    (2008)
  • J.C. Magee

    Observations on clustered synaptic plasticity and highly structured input patterns

    Neuron

    (2011)
  • H. Murakoshi et al.

    Postsynaptic signaling during plasticity of dendritic spines

    Trends Neurosci.

    (2012)
  • C.S. Rex et al.

    Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation

    Neuron

    (2010)
  • L.R. Roth et al.

    Difference in LTP at basal and apical dendrites of CA1 pyramidal neurons in urethane-anesthetized rats

    Brain Res.

    (1995)
  • T.J. Shors et al.

    Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely-moving rat

    Neurosci. Lett.

    (1995)
  • U. Staubli et al.

    Stable hippocampal long-term potentiation elicited by 'theta' pattern stimulation

    Brain Res.

    (1987)
  • P. Vanderklish et al.

    Proteolysis of spectrin by calpain accompanies theta-burst stimulation in cultured hippocampal slices

    Brain Res. Mol. Brain Res.

    (1995)
  • O. Wiggan et al.

    ADF/Cofilin regulates actomyosin assembly through competitive inhibition of myosin II binding to F-actin

    Dev. Cell

    (2012)
  • Q. Zhou et al.

    Reversal and consolidation of activity-induced synaptic modifications

    Trends Neurosci.

    (2004)
  • J.J. Zhu et al.

    Ras and Rap control AMPA receptor trafficking during synaptic plasticity

    Cell

    (2002)
  • W.C. Abraham

    How long will long-term potentiation last?

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (2003)
  • W.C. Abraham et al.

    Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus

    J. Neurosci.

    (2002)
  • A. Arai et al.

    Origins of the variations in long-term potentiation between synapses in the basal versus apical dendrites of hippocampal neurons

    Hippocampus

    (1994)
  • A.C. Arai et al.

    Pharmacology of ampakine modulators: from AMPA receptors to synapses and behavior

    Curr. Drug Targets

    (2007)
  • Babayan, A.H., Kramár, E.A., Barrett, R.M., Jafari, M., Hättig, J., Chen, L.Y., Rex, C.S., Lauterborn, J.C., Wood,...
  • A. Barria et al.

    Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation

    Science

    (1997)
  • M. Bosch et al.

    Structural plasticity of dendritic spines

    Curr. Opin. Neurobiol.

    (2011)
  • K. Braun et al.

    The spacing effect depends on an encoding deficit, retrieval, and time in working memory: evidence from once-presented words

    Memory

    (1998)
  • G. Broutman et al.

    Involvement of the secretory pathway for AMPA receptors in NMDA-induced potentiation in hippocampus

    J. Neurosci.

    (2001)
  • G. Buzsaki

    Theta rhythm of navigation: link between path integration and landmark navigation, episodic and semantic memory

    Hippocampus

    (2005)
  • N.J. Cepeda et al.

    Distributed practice in verbal recall tasks: a review and quantitative synthesis

    Psychol. Bull.

    (2006)
  • L.Y. Chen et al.

    Changes in synaptic morphology accompany actin signaling during LTP

    J. Neurosci.

    (2007)
  • L.Y. Chen et al.

    Learning induces neurotrophin signaling at hippocampal synapses

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

    (2010)
  • Cited by (63)

    • Effects of uninterrupted sinusoidal LF-EMF stimulation on LTP induced by different combinations of TBS/HFS at the Schaffer collateral-CA1 of synapses

      2019, Brain Research
      Citation Excerpt :

      Within 1 h, the second TBS cannot induce further enhancement of LTP levels in the same pathway. On the contrary, there is no such refractory period in HFS-induced LTP (Kramar et al., 2012; Lynch et al., 2013). The results of this paper also prove that the combination of HFS + HFS can further increase LTP.

    • Brain plasticity and sleep: Implication for movement disorders

      2018, Neuroscience and Biobehavioral Reviews
    View all citing articles on Scopus
    View full text