Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location

Abstract

Multiple stimulation protocols have been found to be effective in changing synaptic efficacy by inducing long-term potentiation or depression. In many of those protocols, increases in postsynaptic calcium concentration have been shown to play a crucial role. However, it is still unclear whether and how the dynamics of the postsynaptic calcium alone determine the outcome of synaptic plasticity. Here, we propose a calcium-based model of a synapse in which potentiation and depression are activated above calcium thresholds. We show that this model gives rise to a large diversity of spike timing-dependent plasticity curves, most of which have been observed experimentally in different systems. It accounts quantitatively for plasticity outcomes evoked by protocols involving patterns with variable spike timing and firing rate in hippocampus and neocortex. Furthermore, it allows us to predict that differences in plasticity outcomes in different studies are due to differences in parameters defining the calcium dynamics. The model provides a mechanistic understanding of how various stimulation protocols provoke specific synaptic changes through the dynamics of calcium concentration and thresholds implementing in simplified fashion protein signaling cascades, leading to long-term potentiation and long-term depression. The combination of biophysical realism and analytical tractability makes it the ideal candidate to study plasticity at the synapse, neuron, and network levels.

Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate

“…This term accounts for activity-dependent fluctuations (for more details, see Graupner and Brunel, 2012).…”

Time scales of memory, learning, and plasticity

“…Experiments show that the temporal order is only important in a small regime of presynaptic activation (Sjöström et al 2001) and, furthermore, that synaptic modifications seem to be independent of the spiking of the postsynaptic cell (Golding et al 2002). Thus, alternative models have been developed, for instance, calcium-based plasticity (Lisman 1989;Shouval et al 2002;Yeung et al 2004;Graupner and Brunel 2012).…”

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

“…In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, and at both frequencies, climbing fiber (CF) coactivation promotes LTD, whereas LTP results from PF stimulation alone (6, 7, 15, 16). CF coactivity leads to supralinear spine calcium signaling (17), which helps to reach the calcium threshold for LTD, which is higher than the threshold for LTP at these synapses (6).…”

“…In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).…”