Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (48) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability only was present within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations and to parameter variations. Bistability was robust for molecule numbers plausible for a dendritic spine volume. The upper state of MAPK activity was resistant to inhibition of MEK activation for > 1 h, suggesting inhibitor experiments have not sufficed to rule out a role for persistent MAPK activity in LTP maintenance. These simulations suggest that persistent MAPK activity and consequent upregulation of translation may contribute to LTP maintenance and to long-term memory. Experiments using a fluorescent MAPK substrate may further test this hypothesis.
Deep Dive into Bistable MAP Kinase Activity: A Plausible Mechanism Contributing to Maintenance of Late Long-Term Potentiation.
Bistability of MAP kinase (MAPK) activity has been suggested to contribute to several cellular processes, including differentiation and long-term synaptic potentiation. A recent model (48) predicts bistability due to interactions of the kinases and phosphatases in the MAPK pathway, without feedback from MAPK to earlier reactions. Using this model and enzyme concentrations appropriate for neurons, we simulated bistable MAPK activity, but bistability only was present within a relatively narrow range of activity of Raf, the first pathway kinase. Stochastic fluctuations in molecule numbers eliminated bistability for small molecule numbers, such as are expected in the volume of a dendritic spine. However, positive feedback loops have been posited from MAPK up to Raf activation. One proposed loop in which MAPK directly activates Raf was incorporated into the model. We found that such feedback greatly enhanced the robustness of both stable states of MAPK activity to stochastic fluctuations an
Considerable evidence supports the hypothesis that long-term potentiation (LTP) of synaptic connections is an essential component of memory formation and maintenance (47). This hypothesis implies memories are at least partly stored as patterns of strengthened synapses. The form of LTP relevant for long-term memory, late LTP (L-LTP), lasts for > 3 h and requires protein synthesis (52,68,78). L-LTP can persist for months in vivo (1). An outstanding question is, how can some memories be preserved for months or years given turnover of neuronal and synaptic proteins? Synaptic proteins typically have lifetimes of hours to a few days (19).
To preserve strong synapses, some proposed mechanisms hypothesize bistability in the activity of kinases that, when active, strengthen synapses. A stimulus that induced L-LTP could “switch” a bistable kinase into a persistently active state. MAP kinase (MAPK) activity is necessary for upregulation of dendritic protein synthesis following stimulation by NMDA (28). Bistable activity of the MAPK signaling pathway is thus an interesting candidate mechanism for synaptic strength maintenance, because persistent MAPK activation would tend to upregulate local dendritic translation. Raf is the upstream kinase in the MAPK signaling pathway. Active Raf doubly phosphorylates and activates MEK kinase, which doubly phosphorylates and activates MAPK. Persistent activation of these kinases would lead to phosphorylation and activation of newly synthesized MAPK, thereby counteracting loss of MAPK activity due to protein turnover. Bistability of CaM kinase II autophosphorylation and activity (50) or of PKA activity and AMPA receptor phosphorylation (32) have also been hypothesized to participate in maintenance of synaptic strength.
Bistable MAPK activity has been suggested by experiments with various cell types. Prolonged activation of MAPK is necessary and sufficient for neuronal differentiation of PC-12 cells (15). When PC-12 cells and BHK cells were transfected with active Raf, the increased Raf activity generated all-or-none, binary MAPK activation, suggesting bistability of MAPK activity (30). In the BHK cells, transfection of constitutively active MEK activated endogenous MAPK, but did not activate endogenous MEK, suggesting that in this cell type, there is not positive feedback from MAPK through Raf back to MEK. In further experiments (60), sustained (>1 h) activation of MAPK occurred in PC-12 cells following brief applications of nerve growth factor. Dynamics in which a brief stimulus yields a long-lasting state transition characterize bistability.
These empirical observations motivated us to consider further whether bistable MAPK activity may contribute to maintenance of L-LTP and memory. Some previous modeling studies have hypothesized that bistable MAPK activity is important for the consolidation of L-LTP (8,9,41). However, these models contain a positive feedback loop from MAPK to Raf (via protein kinase C), and thence to MEK (i.e., MAPK activation leads to Raf activation, which activates MEK). Therefore, these models do not explain the bistable MAPK activity observed in BHK cells (30), which occurs in the absence of feedback from MAPK to MEK. In contrast, one recent model (48,54) generates bistable MAPK activity without such feedback. This model was suggested to explain bistable MAPK activity in BHK and PC-12 cells (30). Bistability arises instead from interactions between MAPK and its activating kinase (MEK) and inactivating phosphatase. We therefore began by modifying this model, using parameters that describe more specifically L-LTP induction and the dynamics of neuronal MAPK. We examine whether bistable MAPK activity can plausibly occur at synapses, and whether L-LTP induction might trigger a long-lasting transition to a state of high MAPK activity.
We consider excitatory L-LTP at synapses between pyramidal cells, such as Schaffer collateral (SC) synapses or neocortical synapses. The role of MAPK and of local dendritic translation in this form of L-LTP has been characterized. The MAPK isoforms that appear necessary for L-LTP induction are extracellular-regulated kinase (ERK) 1 and 2 (59). Our model represents postsynaptic activation of the ERK pathway. A range of Raf activity was determined within which simulated ERK activity was bistable. Brief activation of Raf could permanently switch ERK activity from a low state to a high state.
Experiments suggest that the activity of bulk cytoplasmic ERK does not remain elevated for more than 30-45 min after L-LTP induction (20,46, but see 3). Any persistently active ERK would need to be restricted to a small volume, such as a dendritic spine, in order to have avoided detection in those assays. In such small volumes, stochastic fluctuations in molecule numbers may destabilize steady states (10,66,71). Biochemical events important for L-LTP induction and maintenance occur within dendritic spines, which have volumes on the order of 0.1 f
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