Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding

Antunes, Gabriela; Roque, Antônio C.; Souza, Fábio M. Simões de

doi:10.1038/srep23730

Cited by 21 publications

(29 citation statements)

References 56 publications

(98 reference statements)

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“…The range of Ca 2+ rises necessary to induce LTP in the model (0.15–0.4 μmol.L −1 ) was similar to experimental estimations (0.1–0.3 μmol.L −1 ) 2 . We did not observe LTP for stimulations with Ca 2+ pulses of 1 s, which was consequent to the mechanisms of activation of CaN simulated 38 .…”

Section: Resultscontrasting

confidence: 60%

“…Nevertheless, in the cells CaN always occurs as the heterodimer CNB/CNA 41 , consequently, its catalytic activation includes the binding of Ca 2+ to CNB prior to the binding of Ca 2+ /CaM to CNA 28 29 39 . The binding of Ca 2+ to CNB occurred with slow rate constants 29 in our model and limited the activation of CaN for brief signals 38 impairing LTP induction for Ca 2+ pulses of 1 s. Consequently, the kinetic aspects of CaN activation constrained the durations of the Ca 2+ transients 38 that promoted macroscopic LTP ( Fig. 2C ).…”

Section: Resultsmentioning

confidence: 83%

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Stochastic Induction of Long-Term Potentiation and Long-Term Depression

Antunes

Roque

Simões-de-Souza

2016

Sci Rep

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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.

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Section: Resultscontrasting

confidence: 60%

Section: Resultsmentioning

confidence: 83%

Stochastic Induction of Long-Term Potentiation and Long-Term Depression

Antunes

Roque

Simões-de-Souza

2016

Sci Rep

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“…Typically in vitro assays for biological reactions are studied in equilibrium and in controlled conditions. However biological pathways might depend on the dynamics of the signals [38] and the convergence of multiple interactions. In our case AC activation might depend on the timing between CS-US, this dependence can differ greatly from the model, depending on the conditions inside the cell.…”

Section: Model Limitationsmentioning

confidence: 99%

A model for time interval learning in the Purkinje cell

2020

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Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.

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“…AC1 responds to NMDA-mediated calcium elevations (and not calcium released from intracellular stores) and is mostly located close to the post-synaptic densities of dendritic spines [44]. AC1 is the predominant and neuro-specific calcium-stimulated adenylyl cyclase which is mostly expressed in dendrites, axons and at synapses [45]. At very high concentrations of calcium (> 10 µM ) AC1 is inhibited [46].…”

Section: Key Components and Governing Equations Of The Modelmentioning

confidence: 99%

Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines

Ohadi

Schmitt

Calabrese

et al. 2019

Preprint

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Dendritic spines are the primary excitatory postsynaptic sites which act as subcompartments of signaling. Ca 2+ is often the first and rapid signal. Downstream of calcium, the cAMP/PKA pathway plays a critical role in the regulation of spine formation, morphological modifications, and ultimately, learning and memory. While the dynamics of calcium are reasonably well-studied, calcium-induced cAMP/PKA dynamics are not fully explored. In this study, we present a well-mixed model for the dynamics of calcium-induced cAMP/PKA dynamics in dendritic spines. The model is validated against experimental measurements in the literature. Further, we measure calcium dynamics in dendritic spines of cultured hippocampal CA1 neurons to justify the choice of model inputs. Our model predicts that the various steps in this pathway act as a frequency modulator for calcium and high frequency of calcium input is filtered by AC1 and PDEs in this pathway such that cAMP/PKA only responds to lower frequencies. This prediction has important implications for noise filtering and long-timescale signal transduction in dendritic spines. A companion manuscript presents a three-dimensional spatial model for the same pathway. Abbreviations

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Modelling intracellular competition for calcium: kinetic and thermodynamic control of different molecular modes of signal decoding

Cited by 21 publications

References 56 publications

Stochastic Induction of Long-Term Potentiation and Long-Term Depression

Stochastic Induction of Long-Term Potentiation and Long-Term Depression

A model for time interval learning in the Purkinje cell

Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines

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