Abstract
Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. For example, stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, and excess of LPA induce seizures. Further evidence indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA1 which is the most prevalent receptor in human and mouse brain tissue. LPA1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA1 receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA1-deficient mice. In this review, we present an updated account of current evidence pointing to important implications of LPA in the modulation of synaptic excitatory transmission.
Highlights
Phosphatidic acid (PA) or phosphatidate is the simplest phosphoglyceride and the precursor of important glycerophospholipids
But not all, of these effects are mediated through interaction with the LPA1 receptor, considered the most prevalent receptor type in both embryonic and adult brains of humans and mice
Signaling through LPA1 receptor exerts an important impact on KGA expression mainly through a posttranscriptional mechanism, stressing a key relationship between Lysophosphatidic acid (LPA) and glutamatergic transmission
Summary
Phosphatidic acid (PA) or phosphatidate (diacylglycerol 3-phosphate) is the simplest phosphoglyceride and the precursor of important glycerophospholipids. Plasticity-related gene 1 (PRG-1) is a specific membrane protein present at the postsynaptic spines of glutamatergic synapses in the brain cortex and hippocampus, where it has a key role modulating excitability (Vogt et al, 2016).
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