Summary: Phosphatidic acid (PA) is a signaling lipid involved in the modulation of synaptic structure and functioning. Based on previous work showing a decreasing PA gradient along the longitudinal axis of the rodent hippocampus, we asked whether the dorsal hippocampus (DH) and the ventral hippocampus (VH) are differentially affected by PA modulation. Here, we show that phospholipase D1 (PLD1) is a major hippocampal PA source, compared to PLD2, and that PLD1 ablation affects predominantly the lipidome of the DH. Moreover, Pld1 knockout (KO) mice show specific deficits in novel object recognition and social interaction and disruption in the DH-VH dendritic arborization differentiation in CA1/CA3 pyramidal neurons. Also, Pld1 KO animals present reduced long-term depression (LTD) induction and reduced GluN2A and SNAP-25 protein levels in the DH. Overall, we observe that PLD1-derived PA reduction leads to differential lipid signatures along the longitudinal hippocampal axis, predominantly affecting DH organization and functioning. : Santa-Marinha et al. show that PLD1 and PLD2 contribute differentially to the mouse hippocampal lipidomic profile. Their data highlight PLD1-derived PA reduction as a major modulator of dorsal-ventral hippocampal organization and functioning. Keywords: phospholipase D, PLD1, PLD2, dorsal hippocampus, ventral hippocampus, longitudinal hippocampal axis, lipids, lipidomics, long-term depression, social memory
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