De novo lysine myristoylation mediates synaptic plasticity and long-term potentiation through membrane association of synaptic proteins

ABSTRACT: Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs), in particularly myristic acid, from membrane phospholipids via 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 substrate for N-myristoyl transferases (NMT1/2) to drive 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, a response blocked by the DDHD2 inhibitor KLH-45. Inhibition of DDHD2 (KLH-45) or NMT1/2 (IMP-1088) also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning also drives proteomic change in the hippocampus, that are abolished in learning-deficient DDHD2-/- mice. Key synaptic proteins, including 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 acts to mediate synaptic plasticity and memory formation.

INSTRUMENT(S): TripleTOF 5600, ZenoTOF 7600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Layer Of Hippocampus, Cerebral Cortex Neuron, Brain, Cell Culture

SUBMITTER: Benjamin Matthews  

LAB HEAD: Frédéric A. Meunier

PROVIDER: PXD061811 | Pride | 2025-04-22

REPOSITORIES: Pride