Abstract
Cell firing has been reported to variably upregulate or downregulate 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 θ-burst stimulation (TBS) and high-frequency stimulation (HFS) protocols that are known to trigger distinct intracellular signaling 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 θ-burst firing (TBF) or high-frequency firing (HFF) for priming purposes, whereas 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 afterhyperpolarization (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 depolarization and associated Ca
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.
The induction of LTP in the hippocampus was bidirectionally regulated by prior postsynaptic cell firing, with θ-burst stimulation-induced LTP being consistently impaired by prior spiking, whereas high-frequency stimulation-induced LTP was either not changed or facilitated. Reductions in cell firing during LTP induction did not explain the LTP impairment. Overall, different patterns of postsynaptic firing induce distinct intracellular changes that can increase or decrease LTP depending on the induction protocol.