Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability

Rong-Yu Liu,Yili Zhang,John H Byrne,Paul Smolen,Leonard J Cleary

doi:10.1038/s41598-020-57484-y

Abstract

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.

Highlights

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
An Enhanced protocol with irregularly spaced 5-HT applications (Methods) enhances the overlap of PKA and ERK activities upstream of CREB1 and CREB2, and increases long-term synaptic facilitation (LTF) and LTM10,20. We hypothesized that this Enhanced (E) protocol may compensate for the effect of ribosomal S6 kinase (RSK) knockdown by its augmentation of PKA/ERK interaction, normalizing the phosphorylation of CREB1 (pCREB1) and LTF deficits, at least in part
The present study exploited the technical advantages of the Aplysia sensorimotor culture system to examine the roles of RSK in long-term synaptic plasticity and neural excitability

Summary

Veh tRSK

It is likely that this selective block of CREB1 phosphorylation by BID would impair synaptic plasticity To test this hypothesis, LTF was induced by the Standard 5-HT protocol (Fig. 4B1). The EPSP amplitude 24 h post-test increased by 18 ± 6% in the RSK-siRNA + 5-HT group, no significant difference was observed between the RSK-siRNA + Veh and RSK-siRNA + 5-HT groups (q = 1.2, P = 0.4) These results indicate that knockdown of RSK significantly attenuated LTF. We hypothesized that this Enhanced (E) protocol may compensate for the effect of RSK knockdown by its augmentation of PKA/ERK interaction, normalizing the pCREB1 and LTF deficits, at least in part To test this hypothesis, three groups of SN-MN co-cultures were treated with 5-HT (Fig. 6). The Enhanced protocol rescued the BID-induced impairment in LTEE

Discussion

Findings

Materials and Methods