Postsynaptic cell firing bidirectionally regulates future long-term potentiation in the rat hippocampus

Abstract

Synaptic plasticity phenomena such as long-term potentiation (LTP) have been proposed as neurobiological mechanisms of learning and memory. LTP depends on coordinated presynaptic and postsynaptic activity, driven by action potential (AP) firing. While APs serve as the neuronal output signal which integrates different inputs, they can also backpropagate into the dendrites and influence the cell’s own physiology. Such backpropagating APs may act as a retrograde signal to detect the coincidence of presynaptic and postsynaptic activity. Importantly, APs can modulate synaptic plasticity and trigger metaplasticity, a higher-order type of plasticity whereby a neuron’s history of activity changes their ability to undergo subsequent plasticity (a process known as “priming”). AP-induced metaplasticity in the hippocampus, a brain region important for some modes of memory, has, however, been diverse; while some studies suggest that previous AP firing facilitates the induction and maintenance of LTP, others show the opposite. Due to inconsistencies in experimental paradigms used to induce AP-dependent metaplasticity and subsequent LTP, the parameters responsible for facilitating or inhibiting LTP are poorly understood. The aim of this thesis was to elucidate the parameters driving AP-mediated metaplasticity by addressing inconsistencies between previous studies. The main focus was on the influence of different patterns of activity used either to prime or induce LTP, specifically theta-burst stimulation (TBS) and high-frequency stimulation (HFS) which are known to trigger distinct intracellular signalling cascades. It was hypothesised that the metaplastic effects of postsynaptic firing are determined by either the pattern of firing during priming, or the method of LTP induction, or both. This hypothesis was investigated by systematically testing the influence of different experimental parameters on AP-induced metaplasticity, utilising field and intracellular recordings in area CA1 of acute hippocampal slices taken from adult, male Sprague Dawley rats. First, extracellular field recordings were conducted to establish a metaplasticity effect for further comparison. Previously studied patterns of priming stimulation (3x3 TBS, 2x3 HFS) were delivered to CA1 pyramidal cell axons to antidromically activate postsynaptic cells, and LTP was subsequently induced via TBS of CA3-CA1 synapses of stratum radiatum. While antidromic priming by TBS facilitated subsequent LTP, the effect was small. To overcome limitations of field electrophysiology, intracellular sharp-electrode recordings were conducted and cells were primed by somatic current injections using the same priming patterns as for field recordings. In these experiments, TBS-LTP was inhibited by both priming protocols (TBS and HFS), while HFS-LTP was facilitated by HFS priming but not affected by TBS priming. Interestingly, priming reduced AP firing during LTP induction and this effect correlated with the reduction of TBS-LTP. However, this decrease in cell firing itself is unlikely to underlie the metaplasticity effect because LTP was not rescued by restoring AP firing with somatic current injections during induction. Analysis of intrinsic properties revealed a priming-induced increase in the medium after-hyperpolarisation (HFS priming) or a decrease in the EPSP amplitude/slope ratio (TBS priming). These effects may therefore contribute to the inhibition of TBS-LTP by reducing depolarisation and associated Ca2+ influx following synaptic activity or AP backpropagation.