Publication Date
2-1-2024
Journal
The EMBO Journal
DOI
10.1038/s44318-024-00030-7
PMID
38316990
PMCID
PMC10897203
PubMedCentral® Posted Date
2-5-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Mice, Brain, Fatty Acids, Nonesterified, Memory, Memory, Long-Term, Munc18 Proteins, Phospholipases, Lipids, Phospholipase A1, Free Fatty Acids, Myristic Acid, Learning and Memory, Membranes & Trafficking, Metabolism, Neuroscience
Abstract
The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Cognition and Perception Commons, Genetics and Genomics Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Neurology Commons, Neurosciences Commons