Calcium control of triphasic hippocampal STDP

Abstract

Synaptic plasticity is believed to represent the neural correlate of mammalian learning and memory function. It has been demonstrated that changes in synaptic conductance can be induced by approximately synchronous pairings of pre-and post-synaptic action potentials delivered at low frequencies. It has also been established that NMDAr-dependent Calcium influx into dendritic spines represents the critical signal for plasticity induction, and can account for this spike-timing dependent plasticity (STDP) as well as experimental data obtained using other stimulation protocols. However, subsequent empirical studies have delineated a more complex relationship between spike-timing, firing rate, stimulus duration and post-synaptic bursting in dictating changes in the conductance of hippocampal excitatory synapses. It has yet to be established whether the Calcium control hypothesis can account for this more recent data. Here, we present a detailed biophysical model of single dendritic spines on a CA1 pyramidal neuron, describe the NMDAr-dependent Calcium influx generated by different stimulation protocols, and present a parsimonious model of Calcium driven kinase and phosphotase dynamics that dictate transitions between binary synaptic weight states. We demonstrate the manner in which this model can account for various experimental observations of synaptic plasticity and be used to make predictions regarding the dynamics of depolarisation and NMDAr activation generated by STDP protocols as well as the synaptic weight change induced under other experimental conditions. We then discuss how this parsimonious, unified computational model of synaptic plasticity might be utilised to appraise the activity-dependent refinement of neural circuitry induced by more realistic firing patterns. IntroductionSynaptic plasticity -the process of activity dependent change in synaptic conductance -is widely believed to represent the neural correlate of mammalian learning and memory function [1][2][3]. Since the first experimental demonstrations of long-term potentiation (LTP) and depression (LTD), a wealth of empirical data regarding the induction, expression and maintenance of synaptic plasticity in different cortical regions has been obtained [4][5][6][7][8]. In spite of the heterogeneity of plasticity mechanisms observed throughout the brain, changes in the strength of excitatory synapses afferent on CA1 pyramidal neurons in the hippocampus represent the best studied form in the mammalian cortex [9][10][11][12]. At these synapses, Calcium influx into dendritic spines represents the critical signal for synaptic plasticity induction [13][14][15][16][17][18][19][20]. Large, transient elevations in intracellular [Ca 2+ ] generate LTP via the preferential activation of kinase pathways while modest, sustained elevations in intracellular [Ca 2+ ] generate LTD via the preferential activation of phosphotase pathways [21][22][23][24][25]. Initially, empirical observations of synaptic plasticity were mediated by tetanic stimulation protoc...

Calcium: Amplitude, Duration, or Location?

“…The model was tuned to match hippocampal STDP experiments, and then tested using stimulation paradigms other than those used to tune the model. The model was not only able to predict frequency dependent plasticity, but also replicated the observed plasticity due to a variety of other induction protocols such as subthreshold depolarizations and burst pairings (Bush and Jin, 2012). …”

“…Therefore biophysical computational models have been constructed to manipulate calcium amplitude and evaluate frequency-based or STDP-based plasticity rules (Holmes and Levy, 1990; Gold and Bear, 1994; Shouval et al, 2002; Helias et al, 2008; Bush and Jin, 2012; Evans et al, 2012; Cutsuridis, 2013). …”

“…The main problem is revealed through the computational models of calcium-based STDP. Both Shouval et al (2002) and Bush and Jin (2012) show an STDP curve with two windows for LTD. The first window is in the post-pre timing range and matches up with experimental data, but the second window is in the pre-post range between about 70 and 120 ms time difference between the pre-synaptic stimulation and the post-synaptic action potential.…”

Calcium-Dependent Calcium Decay Explains STDP in a Dynamic Model of Hippocampal Synapses

“…STDP has played an important role in revealing the mechanisms underlying plasticity (see [20], [21]), but ‘learning rules’ fit to these data do not easily generalize to deviations from the strict protocols under which the data were recorded (see [22]). In contrast, by simulating the underlying neurophysiology, synaptic models have provided mechanistic explanations for data recorded under different STDP protocols and at different synapses [23]–[30]. The fundamental premise of these models is that a biological variable captures the statistics of pre- and post-synaptic spiking and is used by intracellular signalling pathways to modify synaptic strength accordingly.…”

“…We build on earlier modelling work [23]–[30], [33] by proposing a novel mechanistic explanation for these two requirements for LTP. We hypothesize that these requirements reflect the saturation of the mechanisms underlying extrusion from the post-synaptic spine [34], [35], supporting the buildup of by preventing its decay with sufficiently-vigorous spiking activity.…”