Phospholipases in neuronal function: A role in learning and memory?

Abstract

| LIPIDS AND THE B R AINUnderstanding how the over 80 billion neurons in the human brain communicate with each other to generate a self-aware mind remains one of the great challenges of modern neurobiology. Despite decades of ever more sophisticated study and progress, the molecular mechanisms underpinning the exquisitely regulated neuronal communication at the heart of cognition, learning and memory remain incompletely understood. The discovery that neurotransmission is quantal (Del Castillo and Katz, 1954) led to the development of the vesicle hypothesis in which neurotransmitters are released following fusion of synaptic vesicles with the pre-synaptic membrane in a process known as neuroexocytosis. Decades of subsequent research validated this fundamental finding, and demonstrated the involvement of sophisticated protein machinery (e.g. SNAREs, N-ethylmaleimide-sensitive factor attachment receptors) in all aspects of vesicle trafficking. Most recently, the analysis of brain lipids and lipid metabolites has started to shift this somewhat 'proteocentric' view of neurotransmission to a more holistic view involving tightly regulated protein-protein, protein-lipid (Wenk and De Camilli, 2004) and lipid-lipid interactions, all of which are essential for neuronal communication.Indeed, the healthy human brain is composed of approximately 60% lipid by dry weight, higher than in any other tissue. Seminal chromatography experiments (O'Brien and Sampson, 1965) AbstractDespite the human brain being made of nearly 60% fat, the vast majority of studies on the mechanisms of neuronal communication which underpin cognition, memory and learning, primarily focus on proteins and/or (epi)genetic mechanisms. Phospholipids are the main component of all cellular membranes and function as substrates for numerous phospholipid-modifying enzymes, including phospholipases, which release free fatty acids (FFAs) and other lipid metabolites that can alter the intrinsic properties of the membranes, recruit and activate critical proteins, and act as lipid signalling molecules. Here, we will review brain specific phospholipases, their roles in membrane remodelling, neuronal function, learning and memory, as well as their disease implications. In particular, we will highlight key roles of unsaturated FFAs, particularly arachidonic acid, in neurotransmitter release, neuroinflammation and memory.In light of recent findings, we will also discuss the emerging role of phospholipase A 1 and the creation of saturated FFAs in the brain. K E Y W O R D S exocytosis, free fatty acids, learning, memory, phospholipases, phospholipids, synaptic plasticity | 301 JOENSUU Et al.

Saturated free fatty acids and association with memory formation

“…The vesicular trafficking underpinning these processes involves tightly regulated dynamic modulation of phospholipid membrane fluidity, curvature and surface chemistry in concert with protein/protein and protein/lipid interactions at the pre- and post-synapse 9 , 10 . These processes are mediated in part by the action of specific phospholipases that can locally modify the phospholipid landscape 11 , 12 . This enzymatic phospholipid remodelling generates phospholipid metabolites such as diacylglycerols, inositol triphosphate, lysophospholipids and free fatty acids (FFAs), which can affect membrane dynamics 13 , 14 and act as lipid signalling molecules 15 – 18 .…”

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

“…Our data indicated that SIR affects transcription of several phospholipases, among them four are calcium-dependent: the phospholipase A2 group III (PLA2G3) and group IVE (PLA2G4E), the phospholipase C isoform epsilon-1 (PLCE) and eta-2 (PLCL4). Phospholipases are a family of lipolytic enzymes that regulate composition of cellular membranes, but also play important role in controlling cellular activities [82]. Liberated by phospholipases, arachidonic acid (AA) and its metabolites are significantly engaged in mechanism of learning and memory [83,84]; therefore, substantial changes in their expression may also significantly impact the brain's function.…”

Polar Head Modified Phospholipids by Phospholipase D-Catalyzed Transformations of Natural Phosphatidylcholine for Targeted Applications: An Overview

“…Enzymes with catalytic capacities, similar to cell phospholipases from mammals and plants, are also found in bacteria, and thus, that gives easy access to specific enzymes for practical applications in biocatalysis [40]. Detailed studies of the structure, mechanism and kinetics of phospholipases have been deeply reviewed [41][42][43][44]. All the phospholipases with potential applications are hydrolytic enzymes that are often secreted outside the cell.…”