Smolen2018 - Paradoxical LTP maintenance with inhibition of protein synthesis and the proteasome
Model Identifier
BIOMD0000000853
Short description
This is a mathematical model describing the formation of long-term potentiation (LTP) at the Schaffer collateral of CA1 pyramidal cell synapse. The model consists of nine ordinary differential equations that denote synaptic states associated with different degrees of LTP, as well as the levels of regulatory proteins involved in the formation and maintenance of LTP.
Format
SBML
(L2V4)
Related Publication
-
Paradoxical LTP maintenance with inhibition of protein synthesis and the proteasome suggests a novel protein synthesis requirement for early LTP reversal.
- Smolen P, Baxter DA, Byrne JH
- Journal of theoretical biology , 11/ 2018 , Volume 457 , pages: 79-87 , PubMed ID: 30138630
- Laboratory of Origin: Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Paul.D.Smolen@uth.tmc.edu.
- The transition from early long-term potentiation (E-LTP) to late long-term potentiation (L-LTP) is a multistep process that involves both protein synthesis and degradation. The ways in which these two opposing processes interact to establish L-LTP are not well understood, however. For example, L-LTP is attenuated by inhibiting either protein synthesis or proteasome-dependent degradation prior to and during a tetanic stimulus (e.g., Huang et al., 1996; Karpova et al., 2006), but paradoxically, L-LTP is not attenuated when synthesis and degradation are inhibited simultaneously (Fonseca et al., 2006). These paradoxical results suggest that counter-acting 'positive' and 'negative' proteins regulate L-LTP. To investigate the basis of this paradox, we developed a model of LTP at the Schaffer collateral to CA1 pyramidal cell synapse. The model consists of nine ordinary differential equations that describe the levels of both positive- and negative-regulator proteins (PP and NP, respectively) and the transitions among five discrete synaptic states, including a basal state (BAS), three states corresponding to E-LTP (EP1, EP2, and ED), and a L-LTP state (LP). An LTP-inducing stimulus: 1) initiates the transition from BAS to EP1 and from EP1 to EP2; 2) initiates the synthesis of PP and NP; and finally; 3) activates the ubiquitin-proteasome system (UPS), which in turn, mediates transitions of EP1 and EP2 to ED and the degradation of NP. The conversion of E-LTP to L-LTP is mediated by the PP-dependent transition from ED to LP, whereas NP mediates reversal of EP2 to BAS. We found that the inclusion of the five discrete synaptic states was necessary to simulate key empirical observations: 1) normal L-LTP, 2) block of L-LTP by either proteasome inhibitor or protein synthesis inhibitor alone, and 3) preservation of L-LTP when both inhibitors are applied together. Although our model is abstract, elements of the model can be correlated with specific molecular processes. Moreover, the model correctly captures the dynamics of protein synthesis- and degradation-dependent phases of LTP, and it makes testable predictions, such as a unique synaptic state (ED) that precedes the transition from E-LTP to L-LTP, and a well-defined time window for the action of the UPS (i.e., during the transitions from EP1 and EP2 to ED). Tests of these predictions will provide new insights into the processes and dynamics of long-term synaptic plasticity.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Submitter of this revision: Johannes Meyer
Modellers: Johannes Meyer
Metadata information
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| Smolen2018.xml | SBML L2V4 Representation of Smolen2018 - Paradoxical LTP maintenance with inhibition of protein synthesis and the proteasome | 74.06 KB | Preview | Download |
Additional files |
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| Smolen2018.cps | COPASI file of Smolen2018 - Paradoxical LTP maintenance with inhibition of protein synthesis and the proteasome | 134.34 KB | Preview | Download |
| Smolen2018.sedml | SED-ML file of Smolen2018 - Paradoxical LTP maintenance with inhibition of protein synthesis and the proteasome | 4.89 KB | Preview | Download |
- Model originally submitted by : Johannes Meyer
- Submitted: Nov 12, 2019 6:50:24 PM
- Last Modified: Nov 12, 2019 6:50:24 PM
Revisions
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Version: 2
- Submitted on: Nov 12, 2019 6:50:24 PM
- Submitted by: Johannes Meyer
- With comment: Automatically added model identifier BIOMD0000000853
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| STAB PR:000009238 |
0.01 item |
| EP1 C13281 ; C61589 |
0.18 item |
| UPS PW:0000144 |
0.001 item |
| EP2 C13281 ; C61589 |
0.14 item |
| ED C13281 ; C61589 |
0.01 item |
| LP C13281 ; C25322 |
0.01 item |
| BAS C13281 ; C90067 |
0.96 item |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| STAB => | compartment*kdeg3*STAB | kdeg3 = 0.02 |
| EP1 => BAS | compartment*kb1*EP1 | kb1 = 0.005 |
| => UPS | compartment*kactbas | kactbas = 0.00214 |
| BAS => EP1 | compartment*kf1bas*(1-STIM)*BAS | kf1bas = 0.0; STIM = 1.0 |
| EP2 => ED; UPS | compartment*kf4*UPS*(1-LAC)*EP2 | kf4 = 0.02; LAC = 0.0 |
| EP1 => ED; UPS | compartment*kf2*UPS*(1-LAC)*EP1 | kf2 = 0.02; LAC = 0.0 |
| ED => LP; PP | compartment*kf5*PP^2*ED | kf5 = 5.0E-4 |
| LP => BAS | compartment*kb4*LP | kb4 = 0.001 |
Curator's comment:
(added: 12 Nov 2019, 18:48:37, updated: 12 Nov 2019, 18:48:37)
(added: 12 Nov 2019, 18:48:37, updated: 12 Nov 2019, 18:48:37)
Reproduced plot of Figure 2B in the original publication.
Model simulated and plot produced using COPASI 4.24 (Build 197).