Malleability of Spike-Timing-Dependent Plasticity at the CA3-CA1 Synapse

Abstract

The magnitude and direction of synaptic plasticity can be determined by the precise timing of presynaptic and postsynaptic action potentials on a millisecond timescale. In vivo, however, neural activity has structure on longer timescales. Here we show that plasticity at the CA3-CA1 synapse depends strongly on parameters other than millisecond spike timing. As a result, the notion that a single spiketiming-dependent plasticity (STDP) rule alone can fully describe the mapping between neural activity and synapse strength is invalid. We have begun to explore the influence of additional behaviorally relevant activity parameters on STDP and found conditions under which underlying spike-timing-dependent rules for potentiation and depression can be separated from one another. Potentiation requires postsynaptic burst firing at 5 Hz or higher, a firing pattern that occurs during the theta rhythm. Potentiation is measurable after only tens of presynaptic-before-postsynaptic pairings. Depression requires hundreds of pairings but has less stringent long timescale requirements and broad timing dependence. By varying these parameters, we obtain STDP curves that are long-term potentiation only, bidirectional, or long-term depression only. This expanded description of the CA3-CA1 learning rule reconciles apparent contradictions between spike-timing-dependent plasticity and previous work at CA3-CA1 synapses.

Calcium control of triphasic hippocampal STDP

“…Recent experiments conducted in acute hippocampal slices, which closely approximate the conditions present in vivo, have demonstrated that the plasticity of CA3-CA1 synapses is jointly dependent upon the temporal offset of pre-and post-synaptic firing, number of post-synaptic spikes fired, frequency of spike pairings, and duration of stimulation [28][29][30]. Firstly, we aim to ascertain whether the Calcium control hypothesis -which has been demonstrated to successfully reproduce earlier STDP data obtained in culture (Figure 1a), as well as that induced by other activity patterns -can be revised to account for this joint dependency [18,[41][42][43][44][45][46][47][48].…”

“…The experimental data we aim to replicate can be characterised by considering the effects of two different stimulation protocols -pairing 100 single preand post-synaptic spikes (hereafter referred to as 'spike pairing') at low frequencies (0.1-5Hz), which generates a depression-only learning rule ( Figure 1b); or pairing a single pre-synaptic spike with two post-synaptic spikes (hereafter referred to as 'triplet pairing'), which generates a triphasic bidirectional learning rule after 100 pairings at a frequency of 5Hz (Figure 1c), an unsaturated potentiation-only rule after 30 pairings at 5Hz (Figure 1d), or mild depression after 100 pairings at a frequency of 0.5Hz (data not shown). Each of these data sets can be fitted by a learning rule composed of Gaussian (or a sum of Gaussian) curves centred at short, positive temporal offsets [29]. [26] and (b-d) acute slice preparations [29].…”

“…However, more recent examinations using acute hippocampal slices have been unable to induce bidirectional plasticity with pairs of single preand post-synaptic action potentials under standard recording conditions [ Figure 1b; 28-30, 33, 34]. These results suggest a more complex picture, where synaptic plasticity is dependent not just on relative spike timing, but also on the frequency, duration and nature of spike pairings -with a triphasic STDP curve obtained at CA3-CA1 synapses only when pairings are delivered at approximately theta frequency (>5Hz) and involve multiple post-synaptic spikes [20,29,32; Figure 1c]. Similar results have been obtained at excitatory connections between cortical pyramidal neurons [35].…”

“…Initially, empirical observations of synaptic plasticity were mediated by tetanic stimulation protocols, with high frequency stimulation (HFS; typically 1s of 100Hz afferent firing) used to induce LTP and low frequency stimulation (LFS; typically 15mins of 1Hz afferent firing) used to induce LTD [4,5]. In more recent years, it has also been established that temporally correlated pairs or triplets of pre-and post-synaptic action potentials delivered at low frequencies can induce bidirectional spike-timing dependent plasticity (STDP) depending, among other parameters, on their exact temporal offset over a range of ~100ms [26][27][28][29][30]. STDP has been examined in a variety of cortical regions and species, and its discovery has both accompanied and accelerated a move in computational neuroscience from rate to temporally coded models of cognitive processing [31,32].…”

“…Other experimental data indicates that potentiation and depression events are switch-like transitions between binary conductance states, mediated by kinase and phosphotase pathways that are co-activated and competitive [36][37][38][39][40]. The kinetics of kinase and phosphotase activation also differ significantly, as LTP can be rapidly induced by appropriate patterns of activity while LTD requires prolonged stimulation [15,17,29]. Computational modelling of synaptic plasticity has demonstrated that the dynamics of Calcium influx through the NMDA receptor (NMDAr) is sufficient to account for empirical data obtained using multiple stimulation protocols, integrating an array of experimental results within a single theoretical framework [18,[41][42][43][44][45][46][47][48].…”