Lysophosphatidic Acid and Glutamatergic Transmission

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 LPA 1 which is the most prevalent receptor in human and mouse brain tissue. LPA 1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA 1 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 LPA 1 -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.

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…High levels of LPA have been shown to lessen the size of available vesicle pools at glutamatergic pre-synaptic neurons, thus providing negative feed-back to prohibit the transmission at excitatory synaptic terminals. Nevertheless, in the presence of low concentrations of LPA, inhibitory postsynaptic receptors, namely gamma-aminobutyric acid receptor type A (GABAAR), were internalized to restrain transmission at inhibitory synaptic terminals, thereby briefly increasing the synaptic excitability (García- Morales et al, 2015;Roza et al, 2019). In line with these findings, it is believed that LPA plays a crucial role in modulating glutamatergic transmission in the nervous system.…”

“…Six LPA receptors (LPARs) have been identified : LPA1-LPA6, with genes named LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human; Kihara et al, 2014;Yung et al, 2014Yung et al, , 2015. LPARs have been found to function in neurogenesis and brain development (Castilla-Ortega et al, 2011), neurodifferentiation (Fukushima et al, 2002b;Spohr et al, 2008), neural network formation and morphogenesis (Furuta et al, 2012;Roza et al, 2019), neuroplasticity (Fujiwara et al, 2003;Rhee et al, 2006) and glia cell modulation (Shano et al, 2008;Awada et al, 2014).…”

“…LPARs -Neurodegeneration (Choi and Chun, 2013;Yung et al, 2015). LPA1 G i/o PLC↑, MAPK↑, PI3K/Akt↑, Rac↑ AC↓, cAMP↓ -Neuronal development (Contos et al, 2000;Fukushima et al, 2002a;Kihara et al, 2014;Suckau et al, 2019); -Neurogenesis of adult hippocampus (Fukushima et al, 2002a); -Survival and differentiation of neural progenitor cells (NPCs; Chun et al, 2002;Fukushima et al, 2002a;Yung et al, 2014); -Modulation of adult hippocampus neuroplasticity (García- Morales et al, 2015;Peñalver et al, 2017;Roza et al, 2019); -Negative feedback of microglia induced inflammation (Awada et al, 2014;Kwon et al, 2018).…”

“…Further evidence identified that the LPAR genes are under dynamic regulation throughout mouse brain development, modulating synaptic plasticity in a temporal-and spatial-dependent manner (Suckau et al, 2019). Roza et al (2019) have proposed the underlying mechanism by which LPAR modulates synaptic plasticity. They detected presynaptic glutamate release when stimulating LPAR localized in the presynaptic terminals, whereas excessive LPA stimulation was found to cause seizures (Roza et al, 2019).…”

“…Roza et al (2019) have proposed the underlying mechanism by which LPAR modulates synaptic plasticity. They detected presynaptic glutamate release when stimulating LPAR localized in the presynaptic terminals, whereas excessive LPA stimulation was found to cause seizures (Roza et al, 2019). These results are in line with the observation that LPA modulates the excitatory as well as the inhibitory synapses to regulate synaptic strength and neuronal activity (García- Morales et al, 2015).…”