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Postsynaptic cell firing triggers bidirectional metaplasticity depending on the LTP induction protocol.

Cell firing has been reported to variably up- or down-regulate subsequently induced long-term potentiation (LTP). The aim of this study was to elucidate the parameters critical to driving each direction of the metaplasticity effect. The main focus was on the commonly used theta-burst stimulation (TBS) and high-frequency stimulation (HFS) protocols that are known to trigger distinct intracellular signalling cascades. To study action potential (AP)-induced metaplasticity, we used intracellular recordings from CA1 pyramidal cells of rat hippocampal slices. Somatic current injections were used to induce theta-burst firing (TBF) or high-frequency firing (HFF) for priming purposes, while LTP was induced 15 min later via TBS of Schaffer collaterals in stratum radiatum. TBS-LTP was inhibited by both priming protocols. Conversely, HFS-LTP was facilitated by HFF priming but not affected by TBF priming. Interestingly, both priming protocols reduced AP firing during TBS-LTP induction and this effect correlated with the reduction of TBS-LTP. However, LTP was not rescued by restoring AP firing with somatic current injections during the TBS. Analysis of intrinsic properties revealed few changes, apart from a priming-induced increase in the medium after-hyperpolarisation (HFF priming) and a decrease in the EPSP amplitude/slope ratio (TBF priming) which could in principle contribute to the inhibition of TBS-LTP by reducing depolarisation and associated Ca2+ influx following synaptic activity or AP backpropagation. Overall, these data indicate that the more physiological TBS protocol for inducing LTP is particularly susceptible to homeostatic feedback inhibition by prior bouts of postsynaptic cell firing.