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Review
. 2013 Dec 2;369(1633):20130148.
doi: 10.1098/rstb.2013.0148. Print 2014 Jan 5.

Mechanisms of heterosynaptic metaplasticity

Sarah R Hulme  1 , Owen D Jones, Clarke R Raymond, Pankaj Sah, Wickliffe C Abraham
Affiliations
Review

Mechanisms of heterosynaptic metaplasticity

Sarah R Hulme et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed 'metaplasticity', which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.

Keywords: astrocytes; gap junctions; intercellular signalling; long-term depression; long-term potentiation; metaplasticity.

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Figures

Figure 1.
Figure 1.
BCM-like heterosynaptic metaplasticity. (a) The BCM model [5] posits a synaptic plasticity function whereby a high level of coincident pre- and postsynaptic activity induces LTP, whereas a low level of coincident activity induces LTD. Prior high levels of postsynaptic activity shifts the modification threshold (θM) of the synaptic plasticity function to the right. The converse effect occurs following low levels of postsynaptic activity. Critically, this change in synaptic plasticity induction occurs across all of a cell's synapses regardless of whether they participated in the activity inducing the metaplastic state. (b) Data from the visual cortex support the predictions of the BCM model insofar as dark rearing animals, by reducing the level of activity, causes a leftward metaplastic shift in the synaptic plasticity function. (Adapted and with permission from [6].) (c) A similar effect has been demonstrated in hippocampus slices where, as compared to control conditions (black squares), priming stimulation of one pathway (S1, inset) produces a BCM-like metaplastic shift in subsequent synaptic plasticity both for the stimulated pathway (white squares) and for an independent heterosynaptic pathway (S2, inset) in stratum radiatum (grey squares). (Adapted and with permission from [7].) (d) We have shown that BCM-like heterosynaptic inhibition of stratum radiatum LTP (high-frequency stimulation, Rad. HFS; pathway S2/R2, inset) can also be induced when priming stimulation is delivered in stratum oriens (Or.prime; S1, inset) [8]. (e) Consistent with a BCM-like effect, stratum radiatum LTD (induced by low-frequency stimulation, Rad. LFS) is heterosynaptically facilitated by priming stimulation in stratum oriens. fEPSP, field excitatory postsynaptic potential.
Figure 2.
Figure 2.
Intercellular pathways for heterosynaptic metaplasticity. (a) GABAergic interneurons in the hippocampus can mediate local heterosynaptic facilitation of LTP. Following presynaptic activity (red axon), glutamate (Glu) release and activation of postsynaptic glutamate receptors (GluR), retrograde endocannabinoid (eCB) signalling from the postsynaptic neuron to presynaptic type 1 cannabinoid receptors (CB1R) on GABAergic interneurons persistently reduces GABA release and thus activation of GABAA receptors (GABAAR), thereby facilitating LTP at nearby synapses (green halo, [39]). (b) Another potential intercellular pathway for heterosynaptic metaplasticity involves astrocytes. Long-range signalling through the astrocytic network may alter subsequent synaptic plasticity at distant synapses, including those in different dendritic compartments (left-hand side of figure). Here, for example, activation of inputs to basal dendrites (the red presynaptic axon) results in heterosynaptic metaplasticity (orange halos) in the apical dendrites. Activation of a single astrocyte may also produce heterosynaptic metaplasticity, albeit likely over a more limited spatial extent (right-hand side of figure). The illustrated pathways for intercellular mediation of heterosynaptic metaplasticity are almost certainly not exhaustive. (a) GABAergic interneurons in the hippocampus can mediate local heterosynaptic facilitation of LTP. Following presynaptic activity (red axon), glutamate (Glu) release and activation of postsynaptic glutamate receptors (GluR), retrograde endocannabinoid (eCB) signalling from the postsynaptic neuron to presynaptic type 1 cannabinoid receptors (CB1R) on GABAergic interneurons persistently reduces GABA release and thus activation of GABAA receptors (GABAAR), thereby facilitating LTP at nearby synapses (green halo, [39]).
Figure 3.
Figure 3.
Heterosynaptic metaplasticity in the hippocampal slice is dependent on activation of adenosine A2 receptors. In field potential recordings from CA1 of acute hippocampal slices (refer for methods [40]), LTP (2 × 100 Hz) in stratum radiatum of CA1 is inhibited in slices which first receive priming stimulation (3 × 100 Hz, repeated after 5 min) delivered to stratum oriens afferents (Or.prime). This effect is inhibited by co-administration of the A2AR antagonist ZM241385 and the A2BR antagonist MRS1754 (50 nM each, bar), bath applied prior to and during priming (control: n = 5, 144 ± 4%; primed: n = 8, 122 ± 2%; drug: n = 5, 139 ± 6%, F2,15 = 10.12, p = 0.002). Data are expressed as a percentage of the averaged baseline responses. Arrows denote time-points of oriens priming or radiatum HFS.
Figure 4.
Figure 4.
Heterosynaptic metaplasticity and long-range astrocyte responses are blocked by a gap junction inhibitor. (a) LTP in stratum radiatum is not attenuated by stratum oriens priming stimulation if it occurs in the presence of carbenoxolone (30 µM, black bar: control: n = 6, 130 ± 5%; primed: n = 6, 127 ± 3%, t = 0.53, p = 0.61, n.s.). (b) Following delivery of the same oriens priming stimulation, the average amplitude of astrocytic calcium responses (ΔF/F0) in stratum radiatum was significantly greater in the no drug condition (collapsed across bursts, p < 0.0001; n = 40 cells from seven slices) when compared with the carbenoxolone condition (CBX; n = 23 cells from three slices). For both the no drug and CBX conditions, there was a decline in average amplitude over successive tetani in a burst (p < 0.0001) but no interaction between the condition and tetanus number (p = 0.33). (c) Almost all identifiable astrocytes in stratum radiatum responded (greater than 0.1 increase) to each of the tetani in the no drug condition as compared to only a few cells responding in the presence of carbenoxolone. (d) Excluding astrocytes which did not respond to each of the tetani, the amplitude of responses was still significantly greater in the no drug condition (p < 0.001). Error bars represent s.e.m. Waveforms are from a representative cell from both the no drug (ND) and carbenoxolone (CBX) conditions showing responses to burst 1 and burst 2. Arrows indicate tetanus delivery. Scale bar: amplitude 1, time 10 s. Fluorescence overlay showing SR101 (red) and Fluo-4 (green) (stratum oriens: SO; stratum pyramidale: SP; stratum radiatum: SR). Additional methods for b–d and group numbers for d can be found in the electronic supplementary material.
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References

    1. Brun VH, Ytterbo K, Morris RG, Moser MB, Moser EI. 2001. Retrograde amnesia for spatial memory induced by NMDA receptor-mediated long-term potentiation. J. Neurosci. 21, 356–362 - PMC - PubMed
    1. Migaud M, et al. 1998. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (doi:10.1038/24790) - DOI - PubMed
    1. Abraham WC. 2008. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387–399 (doi:10.1038/nrn2356) - DOI - PubMed
    1. Abraham WC, Bear MF. 1996. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (doi:10.1016/S0166-2236(96)80018-X) - DOI - PubMed
    1. Bienenstock EL, Cooper LN, Munro PW. 1982. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J. Neurosci. 2, 32–48 - PMC - PubMed

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