Abstract
Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory. However, significant gaps exist in the understanding of how interactions among kinase pathways contribute to the mechanistically distinct temporal domains of memory ranging from short-term memory to long-term memory (LTM). Activation of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK)—ribosomal S6 kinase (RSK) pathways are critical for long-term enhancement of neuronal excitability (LTEE) and long-term synaptic facilitation (LTF), essential processes in memory formation. This study provides new insights into how these pathways contribute to the temporal domains of memory, using empirical and computational approaches. Empirical studies of Aplysia sensory neurons identified a positive feedforward loop in which the PKA and ERK pathways converge to regulate RSK, and a negative feedback loop in which p38 MAPK inhibits the activation of ERK and RSK. A computational model incorporated these findings to simulate the dynamics of kinase activity produced by different stimulus protocols and predict the critical roles of kinase interactions in the dynamics of these pathways. These findings may provide insights into the mechanisms underlying aberrant synaptic plasticity observed in genetic disorders such as RASopathies and Coffin-Lowry syndrome.
Highlights
Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory
An electrical shock delivered to the tail, shock of the nerve innervating the tail, or a direct exposure of sensory neurons (SNs) to 5-HT, leads to activation of extracellular signal-regulated kinase (ERK) and p38 M APK11,25,32, but there is a lack of understanding of the dynamics of this activation, and of the dynamics of activation of protein kinase A (PKA) and ribosomal S6 kinase (RSK), which interact with these mitogen-activated protein kinase (MAPK)
Statistical analyses revealed that the increase at 5 min was significant compared to vehicle control (Veh) control, whereas any changes at 15 min (t6 = 0.319, P = 2.28), and 45 min (t7 = 1.142, P = 0.873) were not. These results suggest that one pulse of 5-HT only induced a transient increase in the level of PKA catalytic subunits (PKAc), a fundamentally different time course from phosphorylated RSK (pRSK) (Fig. 1A), pERK25 and phosphorylated p38 MAPK (p-p38 MAPK)[11]
Summary
Kinases play critical roles in synaptic and neuronal changes involved in the formation of memory. RSK in Aplysia is activated by the MEK/ERK pathway and RSK activity contributes to 5-HT-induced phosphorylation of the transcription activator cAMP response element binding protein 1 (CREB1), as well as L TF23 These new findings raise the possibility that other interactions are present and contribute to the dynamics of kinases and induction and consolidation of LTF and LTEE. Two new pathways were identified: PKA-dependent, but ERK-independent, regulation of RSK activity, and RSK-dependent activation of p38 MAPK These data and other recent results were used to extend our previous computational model of multiple molecular cascades underlying LTF and LTEE. The model simulates kinase activation after different training regimens, maintains the predictive ability of the previous model[28], and prompts new predictions validated by subsequent experiments
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