Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors

Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs) -particularly myristic acid- from membrane phospholipids by the phospholipase A1 isoform DDHD2. However, the mechanism through which myristic acid contributes to synaptic plasticity remains elusive. Here we demonstrate that DDHD2-derived myristic acid is rapidly converted to myristoyl CoA, which serves as the substrate for N-myristoyl transferases (NMT1/2), to promote post-translational lysine myristoylation of synaptic proteins. Chemically-induced long-term potentiation (cLTP) in cortical neurons increases both sFFAs and their CoA-conjugates, predominantly myristoyl CoA, and this response is blocked by the DDHD2 inhibitor KLH-45. KLH-45-mediated inhibition of DDHD2 or IMP-1088-mediated inhibition of NMT1/2 also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning further induces proteomic changes in the hippocampus, which are abolished in learning-deficient DDHD2^-/- knockout mice. In these mice, key synaptic proteins such as NMDA receptor subunit GluN1, MAP2, and GAS7 fail to undergo learning-induced changes, effectively linking DDHD2 function to learning-dependent proteome remodeling. Our findings reveal that de novo lysine myristoylation promotes synaptic plasticity and memory formation.