Calcium-Dependent But Action Potential-Independent BCM-Like Metaplasticity in the Hippocampus

Abstract

The Bienenstock, Cooper and Munro (BCM) computational model, which incorporates a metaplastic sliding threshold for LTP induction, accounts well for experience-dependent changes in synaptic plasticity in the visual cortex. BCM-like metaplasticity over a shorter timescale has also been observed in the hippocampus, thus providing a tractable experimental preparation for testing specific predictions of the model. Here, usingextracellularandintracellularelectrophysiologicalrecordingsfromacuterathippocampalslices,wetestedthecriticalBCMpredictions (1) that high levels of synaptic activation will induce a metaplastic state that spreads across dendritic compartments, and (2) that postsynaptic cell-firing is the critical trigger for inducing that state. In support of the first premise, high-frequency priming stimulation inhibited subsequent long-term potentiation and facilitated subsequent long-term depression at synapses quiescent during priming, including those located in a dendritic compartment different to that of the primed pathway. These effects were not dependent on changes in synaptic inhibition or NMDA/ metabotropic glutamate receptor function. However, in contrast to the BCM prediction, somatic action potentials during priming were neither necessary nor sufficient to induce the metaplasticity effect. Instead, in broad agreement with derivatives of the BCM model, calcium as released fromintracellularstoresandtriggeredbyM1muscarinicacetylcholinereceptoractivationwascriticalforalteringsubsequentsynapticplasticity. These results indicate that synaptic plasticity in stratum radiatum of CA1 can be homeostatically regulated by the cell-wide history of synaptic activity through a calcium-dependent but action potential-independent mechanism.

Mechanisms of heterosynaptic metaplasticity

“…To address this, we have undertaken calcium imaging of CA1 astrocytes filled with Fluo-4 and labelled with sulforhodamine-101 by injection of these compounds directly into the hippocampus prior to slice preparation (see electronic supplementary material). Using the same stratum oriens stimulation parameters that inhibit LTP and promote LTD in stratum radiatum (6 Â 100 Hz, 1 s trains [8]), we observed that each highfrequency train of priming stimulation reliably induced a calcium elevation not only in stratum oriens astrocytes (not shown), but also in stratum radiatum astrocytes as far from the cell body layers as was imaged (297 mm; mean 87 + 10 mm; figure 4b,d). The greatest increase occurred in response to the first high-frequency stimulation (HFS) in a set of three trains (20 s apart).…”

“…Interestingly, regulation of GABAergic transmission was not a mediator of the cell-wide heterosynaptic metaplasticity we have recently described [8]. Instead, we identified two other signalling mechanisms, both of which are commonly implicated in intercellular communication.…”

“…Overall, the BCM theory has been hugely influential in the plasticity field by formalizing testable predictions not only about the direction and degree of plasticity arising from conjunctive pre-and postsynaptic activity, but also about the activitydependent regulation of the LTP threshold. These predictions have been confirmed, at least in part, by studies in the visual cortex and hippocampus [6][7][8][9][10].…”

“…B 369: 20130148 subsequent synaptic plasticity in a BCM-like manner [9,11]. However, under other conditions, cell firing is neither necessary nor sufficient for BCM-like heterosynaptic metaplasticity [8,12]. In fact, cell firing in these cases facilitated rather than inhibited subsequent LTP.…”

“…For example, we recently described a heterosynaptic metaplasticity that spread from basal to apical dendrites in CA1 pyramidal neurons, without requirement for action potential generation or even somatic depolarization [8]. We identified activation of M1-acetylcholine receptors (M1-AChRs) and IP 3 -mediated release of Ca 2þ from intracellular stores as contributing mechanisms.…”