Abstract
Long-term depression (LTD) and long-term potentiation (LTP) of granule-Purkinje cell synapses are persistent synaptic alterations induced by high and low rises of the intracellular calcium ion concentration ([Ca2+]), respectively. The occurrence of LTD involves the activation of a positive feedback loop formed by protein kinase C, phospholipase A2, and the extracellular signal-regulated protein kinase pathway, and its expression comprises the reduction of the population of synaptic AMPA receptors. Recently, a stochastic computational model of these signalling processes demonstrated that, in single synapses, LTD is probabilistic and bistable. Here, we expanded this model to simulate LTP, which requires protein phosphatases and the increase in the population of synaptic AMPA receptors. Our results indicated that, in single synapses, while LTD is bistable, LTP is gradual. Ca2+ induced both processes stochastically. The magnitudes of the Ca2+ signals and the states of the signalling network regulated the likelihood of LTP and LTD and defined dynamic macroscopic Ca2+ thresholds for the synaptic modifications in populations of synapses according to an inverse Bienenstock, Cooper and Munro (BCM) rule or a sigmoidal function. In conclusion, our model presents a unifying mechanism that explains the macroscopic properties of LTP and LTD from their dynamics in single synapses.
Highlights
Long-term depression (LTD) and long-term potentiation (LTP) are persistent activity-dependent modifications of the synaptic strength[1]
protein kinase C (PKC) counteracted the action of CaN on endocytic protein (EP). (C) Simulation of the percentage of AMPARsyn at rest. (D) LTD expression consisted of a persistent reduction of AMPARsyn. (E) During LTP, the model simulated an increase in the percentage of AMPARsyn
We simulated LTD with the positive feedback loop formed by PKC, phospholipase A2 (PLA2), and extracellular signal-regulated protein kinase (ERK) pathway, which we expanded and updated from a previous version[14] based on early models of synaptic plasticity[3,16]
Summary
Long-term depression (LTD) and long-term potentiation (LTP) are persistent activity-dependent modifications of the synaptic strength[1]. The induction of LTD involves simultaneous stimulations of parallel fibres and climbing fibres at low frequency (~1 Hz), which promote large elevations of the intracellular calcium ion concentration ([Ca2+])[1,2], and activate a positive feedback loop formed by protein kinase C (PKC), cytosolic phospholipase A2 (PLA2), and the extracellular signal-regulated protein kinase (ERK) pathway[3,4]. Granule-Purkinje cells synapses exhibit postsynaptic LTP induced by repetitive activations of the parallel fibres at low frequency (1 Hz), which cause low Ca2+ transients[1,2]. A limitation of this earlier model is that it did not simulate mechanisms implicated with LTP, which could reveal a more complex scenario involving Ca2+ and the long-lasting forms of synaptic plasticity. The arrows indicate LTD and LTP induction with a Ca2+ pulse of 3 μmol.L−1 and 0.35 μmol.L−1, respectively, and 30 s of duration
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