Invited reviewDifferences between synaptic plasticity thresholds result in new timing rules for maximizing long-term potentiation
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.).
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