Defective synaptic plasticity in a model of Coffin-Lowry Syndrome is rescued by simultaneously targeting PKA and MAPK pathways

Empirical and computational methods were combined to examine whether individual or dual-drug treatments can restore the deficit in long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse observed in a molecular model of Coffin-Lowry Syndrome (CLS). The model was produced by pharmacological inhibition of p90 ribosomal S6 kinase (RSK) activity. Simultaneous treatment with an activator of the mitogen-activated protein kinase (MAPK) isoform ERK and an activator of protein kinase A (PKA) resulted in enhanced phosphorylation of RSK and LTF to a greater extent than either drug alone and greater than their additive effects. Indeed, the combined drugs exerted synergistic effects on both RSK activation and LTF, fully restoring RSK phosphorylation and LTF. The extent of synergism appeared to depend on another MAPK isoform, p38 MAPK. Inhibition of p38 MAPK facilitated serotonin (5-HT)-induced RSK phosphorylation, indicating that p38 MAPK inhibits activation of RSK. Inhibition of p38 MAPK combined with activation of PKA synergistically activated RSK.