We used targeted FFAST lipidomics coupled with a reward-based long-term memory paradigm to demonstrate that the DDHD2 isoform of PLA1 is critical for driving saturated FFA responses to memory acquisition, with its knockout, a model for human spastic paraplegia, causing ablation of saturated FFAs and leading to the progressive decline in memory and neuromuscular performance. Here, DDHD2 is linked to Spastic paraplegia.