Questions about STDP as a General Model of Synaptic Plasticity.

According to spike-timing-dependent plasticity (STDP), the timing of the Na(+) spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na(+) spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na(+) spikes does not necessarily prevent LTP induction. Thus, Na(+) spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca(2+) spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na(+) spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD.

It is well established that depolarization of the postsynaptic neuron can promote LTP by allowing the activation of NMDA receptors. Furthermore, smaller depolarizations may be necessary for the induction of LTD. Given this role of postsynaptic voltage in plasticity, it is important to establish how such depolarization is generated. According to the literal interpretation of Hebb's postulate, postsynaptic action potentials produce the required depolarization. This idea has been made plausible by the finding (Stuart and Sakmann, 1994) that action potentials backpropagate from the soma into the dendrite and can thus affect the synapses there.

The field of STDP developed after the observation that the timing of backpropagating Na+ spikes relative to the EPSP can determine the sign of synaptic plasticity (reviewed in Caporale and Dan, 2008). It is thus now widely assumed that such spikes are critical in the synaptic plasticity process; indeed, this assumption is the basis of numerous theoretical models. However, there are serious reasons to doubt whether spike timing is a major determinant of synaptic plasticity. Almost all experiments demonstrating STDP have been done under conditions in which the experimenter induces the postsynaptic spike by current injection. If STDP is an important phenomenon, it must also apply when the spike is evoked naturally by the EPSP. In a previous review, we presented a critique of STDP, questioning whether it occurs under such natural conditions (Lisman and Spruston, 2005). We thank the editors of this volume for inviting us to summarize this critique here. In the interest of brevity, we express our concerns about STDP in a series of short questions/answers. Readers wanting additional information should consult our previous review.

Question: Is a Na+ spike necessary for synaptically induced LTP? Answer: Eliminating the spike often has no effect (Golding et al., 2002; Remy and Spruston, 2007; Hardie and Spruston, 2009).

Question: Does the lack of a requirement for the Na+ spike make sense? Answer: Yes, because dendritic recordings show that backpropagating action potentials are always brief and often small (especially in distal dendrites) compared to other forms of dendritic depolarization (Stuart et al., 1997).

Question: Are Na+ spikes necessary for synaptically induced LTD? Answer: Not in general. LTD can be induced following low-frequency stimulation with or without spikes (Dudek and Bear, 1992; Sjöström et al., 2001; Staubli and Ji, 1996; Wittenberg and Wang, 2006). Na+ spikes tend to enhance LTD, despite the fact that according to STDP the pre-before-post timing predicts LTP.

Question: Perhaps the spike is unimportant during synaptically induced LTP/LTD, but doesn't the spike do the job in STDP protocols (when the spike is induced by current injection)? Answer: The repetition rates typically used are so high that other types of dendritic events such as Ca spikes may be inadvertently induced by summation of EPSPs, complicating the interpretation. If lower repetition rates are used, single spikes no longer induce LTP/LTD unless larger EPSPs are used, suggesting the importance of additional sources of depolarization (Sjöström et al., 2001).

Question: Theoretical work has shown that the causal role of the presynaptic spike in generating the EPSP, which then generates the postsynaptic spike, is an elegant principle; should this concept be revised? Answer: Yes, there are cases in which the EPSP evokes a spike, but the result is LTD, not LTP (see question 3) and there are cases when the spike is not necessary for LTP (see question 1). Thus, spike timing is probably not the best approach to modeling synaptic plasticity (see below).

Question: Theoretical work has shown that the timing relation of presynaptic and postsynaptic events can produce important computations; should this be given up? Answer: No. Timing will inevitably be important because of the properties of the NMDA receptor (depolarization before glutamate binding doesn't open the channel, whereas the reverse order does). When we learn what the critical depolarizing event is (or are), timing will certainly be important.

Question: If the backpropagating spike is not the critical factor for synaptic plasticity, what is? Answer: The AMPA-mediated EPSP, NMDA receptor-mediated plateau potentials, and dendritically initiated Ca spikes are plausible candidates (Gordon et al., 2006; Kampa et al., 2007).

Question: Isn't STDP elegant because of its computational consequences? Answer:No, it isn't as elegant as it may seem because information can't be read out (by EPSP-evoked spikes) without modifying stored information. If there is a higher threshold for plasticity (e.g., bursts or calcium spikes), it becomes possible to read out information using single spikes without modifying stored information.

Question: How is the critical source of the postsynaptic depolarization required for plasticity going to be determined? Answer: It's a hard problem. Some of the most advanced methods (paired recording and glutamate uncaging) will not suffice because they don't stimulate inhibition. Given the likely role of voltage-dependent conductances (including NMDA receptors), the occurrence and duration of depolarizing events will depend strongly on inhibition, which must therefore be part of the overall story (Davies et al., 1991; Remondes and Schuman, 2002).

We are encouraged by a recent model that explains a wide range of experimental observations using an approach that does not focus on the backpropagating action potential as the sole source of dendritic depolarization (Clopath et al., 2010). Using a combination of factors related to the pre and postsynaptic membrane potentials (see also Spruston and Cang, 2010), the model explains the dependence of LTP/LTD on stimulus frequency, postsynaptic bursting, and the synaptic depolarization. Future implementations of the model could seek to explain the dependence of synaptic plasticity on specific biophysical events, such as dendritic spikes and inhibition, in compartmental models of neurons with elaborate dendritic trees endowed with a variety of conductances. It will also be of interest to see whether this class of model can also explain why the phase of synaptic stimulation during theta frequency oscillations can determine whether LTP or LTD is induced (Huerta and Lisman, 1995; Hyman et al., 2003; Kwag and Paulsen, 2009).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.