Lipid-fuelled synaptic plasticity: integrating membrane turnover, β-oxidation, and protein lipidation

Synaptic plasticity requires the coordinated regulation of membrane remodelling, energy production, and protein turnover. However, how these processes are integrated at the molecular level remains unclear. Here, we propose that activity-dependent lipid flux represents a central mechanism linking these processes. Saturated free fatty acids (sFFAs) released from membrane phospholipids, triglycerides, or from extracellular uptake can be activated to acyl-CoA and directed to mitochondrial β-oxidation and synaptic protein lipidation. These represent two emerging pathways adding to the complexity of roles played by sFFAs, including membrane fluidity and receptor activation. Recent work identifies DDHD2 as a mechanistic entry point into this broader synaptic lipid network. We position DDHD2-dependent lipid mobilisation in the wider context of glia-neuron lipid transfer and ApoE/sortilin-dependent fatty acid uptake. Key unresolved questions include the source and fate of fatty acids, the relative contribution of β-oxidation versus glycolysis to ATP production, and whether these pathways are altered in neurodegenerative disease.