Search

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., (© 2021. The Author(s).)

Multiple kinases converge on the transcription factor cAMP response element-binding protein (CREB) to enhance the expression of proteins essential for long-term synaptic plasticity and memory. The p90 ribosomal S6 kinase (RSK) is one of these kinases, although its role is poorly understood. The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the role of RSK in long-term synaptic facilitation (LTF) and long-term enhancement of neuronal excitability (LTEE), two correlates of long-term memory (LTM). Inhibition of RSK expression or RSK activity both significantly reduced CREB1 phosphorylation, LTF, and LTEE, suggesting RSK is required for learning-related synaptic plasticity and enhancement in neuronal excitability. In addition, knock down of RSK by RNAi in Aplysia sensory neurons impairs LTF, suggesting that this may be a useful single-cell system to study aspects of defective synaptic plasticity in Coffin-Lowry Syndrome (CLS), a cognitive disorder that is caused by mutations in rsk2 and associated with deficits in learning and memory. We found that the impairments in LTF and LTEE can be rescued by a computationally designed spaced training protocol, which was previously demonstrated to augment normal LTF and LTM.

Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.

Learning and memory are influenced by the temporal pattern of training stimuli. However, the mechanisms that determine the effectiveness of a particular training protocol are not well understood. We tested the hypothesis that the efficacy of a protocol is determined in part by interactions among biochemical cascades that underlie learning and memory. Previous findings suggest that the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) cascades are necessary to induce long-term synaptic facilitation (LTF) in Aplysia, a neuronal correlate of memory. We developed a computational model of the PKA and ERK cascades and used it to identify a training protocol that maximized PKA and ERK interactions. In vitro studies confirmed that the protocol enhanced LTF. Moreover, the protocol enhanced the levels of phosphorylation of the transcription factor CREB1. Behavioral training confirmed that long-term memory also was enhanced by the protocol. These results illustrate the feasibility of using computational models to design training protocols that improve memory.

Learning can lead to changes in the intrinsic excitability of neurons. However, the extent to which these changes persist and the role they have in the expression of memory remain unclear. We found that in vitro analogs of operant conditioning produced a long-term (24 h) increase in the excitability of an identified neuron (B51) that is critical for the expression of feeding in Aplysia. This increase in excitability, which was cAMP dependent, contributed to the associative modification of the feeding circuitry, providing a mechanism for long-term memory., Competing Interests: statement: The authors declare that they have no competing financial interests.

A long-standing debate in neuroscience is whether classical and operant conditioning are mechanistically similar or distinct. The feeding behavior of Aplysia provides a model system suitable for addressing this question. Here we report that classical and operant conditioning of feeding behavior differentially modify the intrinsic excitability of neuron B51, a critical element for the expression of the feeding response, thus revealing that these two forms of associative learning differ at the cellular level.