Saturated free fatty acids and association with memory formation

Tristan P Wallis,Pankaj Sah,Alan Ho,Bharat G Venkatesh,David Kvaskoff,François Windels,Vinod K Narayana,Frédéric A Meunier,Robert K Sullivan

doi:10.1038/s41467-021-23840-3

Abstract

Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. However, the precise nature of other FFA and phospholipid changes in specific areas of the brain during learning is unknown. Here, using a targeted lipidomics approach to characterise FFAs and phospholipids across the rat brain, we demonstrated that the highest concentrations of these analytes were found in areas of the brain classically involved in fear learning and memory, such as the amygdala. Auditory fear conditioning led to an increase in saturated (particularly myristic and palmitic acids) and to a lesser extent unsaturated FFAs (predominantly arachidonic acid) in the amygdala and prefrontal cortex. Both fear conditioning and changes in FFA required activation of NMDA receptors. These results suggest a role for saturated FFAs in memory acquisition.

Highlights

Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity
Using our lipidomics approach in conjunction with auditory fear conditioning (AFC), we have demonstrated that (i) the distribution of phospholipids and FFAs is heterogeneous across the rat brain, with the highest concentrations being found in the amygdala, (ii) phospholipid and FFA profiles change across the brain in response to AFC in an activitydependent manner, (iii) these changes are characterized by increases in saturated FFAs and to a lesser degree unsaturated FFAs potentially released from phospholipid substrates, and (iv) blocking these changes with the NMDA receptor antagonist CPP correlates with a failure of long-term memory consolidation but has no effect on short-term responses to AFC
Together our results suggest that FFA changes regulated by NMDA receptors are required for learning and memory formation

Summary

Introduction

Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. We applied a targeted LCMS lipidomic workflow to quantify the responses of 135 phospholipid species belonging to 5 different classes This combined approach revealed that the highest phospholipid and FFA concentrations, relative to tissue weight, are in the amygdala and prefrontal cortex, and that these are dramatically modified by fear conditioning. These FFA changes were largely driven by long chain saturated FFAs such as myristic and palmitic acids, and were not seen when learning was inhibited by using the NMDA receptor antagonist CPP. Together these data suggest that phospholipid-derived FFA increases play an unexpected and critical role in learning and memory formation

Methods

Results

Conclusion