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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Neuron. Author manuscript; available in PMC Jul 14, 2012.
Published in final edited form as:
PMCID: PMC3143314
NIHMSID: NIHMS310448
TIMING IS EVERYTHING, EVEN FOR CHOLINERGIC CONTROL
Darwin K. Berg1*
1Division of Biological Sciences; University of California, San Diego; La Jolla, CA 92093-0357
* Correspondence: dberg/at/ucsd.edu
Abstract
Synaptic plasticity is widely considered to be a cellular mechanism underlying learning and memory. In this issue of Neuron, Gu and Yakel show that the precise timing of a single cholinergic pulse of activity can determine whether plasticity will occur at a glutamatergic synapse and confer long-term potentiation versus depression.
Activity-dependent plasticity at synapses formed by Schaffer collaterals (SCs) onto CA1 pyramidal neurons in the hippocampus represents the most studied and best understood cellular model for learning and memory to date. This has been driven in part by the simplicity and accessibility of the tri-synaptic excitatory pathway through the hippocampus, and in part by the relevance of the hippocampus in that it is essential for encoding new declarative memories. Two forms of synaptic plasticity that have received a great deal of attention are long-term potentiation (LTP) and long-term depression (LTD). These have been analyzed at the molecular level and shown to depend on glutamatergic input through postsynaptic NMDA receptors, calcium influx, and downstream signaling pathways in the postsynaptic neuron (Malenka, 2003; Collingridge et al., 2010).
Cholinergic transmission, employing the transmitter acetylcholine (ACh) to activate ligand-gated ion channels (nicotinic ACh receptors, nAChRs) and G protein-coupled muscarinic receptors (mAChRs), is known to be critical for cognitive function (Reis et al., 2009). Cholinergic deficits contribute to a number of cognitive diseases, including Alzheimer’s and Parkinson’s diseases, as well as schizophrenia (Kenney and Gould, 2008). Cholinergic input to the hippocampus comes primarily from the septum and is thought to be important for modulating synaptic plasticity. Numerous studies have shown that nicotine or ACh applied acutely to the CA1 can promote synaptic plasticity. This usually results from presynaptic nAChRs enhancing glutamate or GABA release, but can also be mediated by postsynaptic nAChRs and muscarinic receptors acting through other mechanisms (Ji et al., 2001; Ge and Dani, 2005; Buchanan et al., 2010).
A limitation of many studies on synaptic plasticity, however, is that they usually employ high frequency stimulation of synaptic inputs to induce LTP or LTD and then assess the effects of modulatory compounds such as nicotine. Tetanic stimulation of this kind may not represent a good synaptic model for learning. It is now clear that the exact timing of an individual presynaptic action potential relative to postsynaptic depolarization is critical for determining the long-lasting outcome (Dan and Poo, 2004). How endogenous cholinergic input might modulate this spike timing-dependent plasticity is unknown.
Gu and Yakel (2011) in this issue of Neuron report an elegant series of experiments in which they analyze the timing required for cholinergic modulation of synaptic plasticity. They use single pulses of stimulation to activate SCs and elicit postsynaptic currents (PSCs) in CA1 pyramidal neurons while at the same time stimulating the stratum oriens (SO) with single pulses to activate cholinergic input from the septum to the CA1. By varying the timing of SC and SO stimulation, Gu and Yakel obtain qualitatively different outcomes. As few as 5–10 pairings at low frequency (0.033 Hz) enabled the cholinergic input to induce robust LTP if the SO stimulation preceded the SC stimulation by 100 ms. Longer or shorter intervals were ineffective at this; an interval as short as 10 ms, however, induced a different form of plasticity, short-term depression (STD). Inverting the sequence and shortening the duration such that SC stimulation preceded SO stimulation by 10 ms produced robust LTP. Longer times were ineffective both for LTP and STD. The authors point out that this timing dependence enables a single cholinergic input not only to determine the kind of plasticity a synapse undergoes but also to determine the synapses affected, thereby constraining the plasticity spatially to those synapses active within the requisite time window (Fig. 1).
Figure 1
Figure 1
Schematic showing the timing dependence of cholinergic input from the septum in determining the kinds of synaptic plasticity found at glutamatergic synapses formed by SCs onto CA1 pyramidal neurons in the hippocampus. (A) Diagram showing the cholinergic (more ...)
The molecular mechanisms mediating the two forms of LTP utilize different pathways. Both LTP and STD induced by SO stimulation preceding SC stimulation depended on activation of nAChRs containing the α7 subunit (α7-nAChRs). LTP induced by the reverse order of stimulation was mediated by mAChRs. Both forms of LTP appear to depend on postsynaptic changes. This was inferred by analyzing the paired-pulse ratio (PPR), i.e. the relative amplitudes of two closely-spaced PSCs; the PPR showed no change in response to LTP induction. Lack of change in the PPR is usually interpreted to mean that the probability of transmitter release has not changed, implying by default that the change underlying the LTP must be postsynaptic. The mechanisms employed by α7-nAChRs to induce LTP rely on some of the same mechanisms used by NMDA receptors for this purpose, namely activation of NMDA receptors, influx of calcium, and insertion of GluR2-containing AMPA receptors into the postsynaptic membrane.
Importantly, Gu and Yakel used optogenetics to demonstrate that the dependence of LTP induction on the timing of SO stimulation solely reflected the consequences of activating the cholinergic input. They did this by using mice in which channelrhodopsin-2 was expressed only in cholinergic neurons (those expressing choline acetyltransferase) in the medial septal nuclei. They were then able to use laser illumination to activate selectively cholinergic inputs to the CA1 with, at most, a 20 ms delay. Using this preparation they were able to replicate the results obtained with electrical stimulation, namely that triggering cholinergic input 100 ms (plus the 20 ms delay) before SC stimulation resulted in LTP, as did cholinergic activation 10 ms after SC stimulation. Cholinergic activation at other times did not support LTP. And, as with the electrical stimulation experiments, pharmacological analysis indicated that the laser-activated cholinergic input employed α7-nAChRs to trigger LTP when arriving 100 ms before the SC input, and mAChRs to induce LTP when arriving 10 ms after the SC input.
In a final set of experiments Gu and Yakel tested the effects of β-amyloid peptide (Aβ) on time-dependent cholinergic modulation of synaptic plasticity. Cholinergic decline is an early feature of Alzheimer’s disease, and Aβ has previously been shown to inhibit α7-nAChR function (Liu et al., 2001). They find that the timing-dependent induction of LTP by α7-nAChRs is highly sensitive to blockade by Aβ. This suggests a mechanism by which Aβ may impair cognitive function by disrupting cholinergic control of synaptic plasticity.
Interesting follow-up questions immediately emerge, ranging from the molecular to the behavioral. At one extreme is the question of how cholinergic input through α7-nAChRs promotes LTP. Although the authors show that the mechanisms downstream of α7-nAChRs are similar to those employed by NMDA receptors to induce LTP, it is less clear whether the α7-nAChRs act presynaptically, enhancing glutamate release at the critical time, or act postsynaptically, possibly providing crucial calcium influx at the right time and place. The α7-nAChR has a high relative calcium permeability which facilitates activation of local calcium-dependent pathways (Albuquerque et al., 2009). Gu and Yakel measured calcium influx and did not detect an independent α7-nAChR component in the postsynaptic cell. It is possible, however, that the α7-nAChR component, though below the limits of experimental detection, still contributed by promoting calcium-induced calcium release from internal stores or acting locally to reach a critical threshold. The convergence of cholinergic and SC input did synergistically increase the amount of postsynaptic calcium, but the sources have yet to be determined.
An exciting question at the other end of the complexity spectrum is whether the synaptic plasticity mediated by cholinergic input observed here has behavioral consequences. The ability to activate the cholinergic pathway in vivo with optogenetics, coupled with new strategies for performing learning tests on alive, awake, behaving mice (Komiyama et al., 2010), suggests compelling experiments for the future. It should be possible to define unambiguously the contributions of cholinergic input, coupled with spike timing-dependent plasticity, to learning and memory, and to elucidate the critical cellular and molecular mechanisms that are involved in these processes.
Footnotes
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