Abstract
Lysophosphatidic acid (LPA) is an important bioactive lipid species that functions in intracellular signaling through six characterized G protein-coupled receptors (LPA1-6). Among these receptors, LPA1 is a strong candidate to mediate the central effects of LPA on emotion and may be involved in promoting normal emotional behaviors. Alterations in this receptor may induce vulnerability to stress and predispose an individual to a psychopathological disease. In fact, mice lacking the LPA1 receptor exhibit emotional dysregulation and cognitive alterations in hippocampus-dependent tasks. Moreover, the loss of this receptor results in a phenotype of low resilience with dysfunctional coping in response to stress and induces anxiety and several behavioral and neurobiological changes that are strongly correlated with mood disorders. In fact, our group proposes that maLPA1-null mice represent an animal model of anxious depression. However, despite the key role of the LPA-LPA1-pathway in emotion and stress coping behaviors, the available information describing the mechanisms by which the LPA-LPA1-pathway regulates emotion is currently insufficient. Because activation of LPA1 requires LPA, here, we used a Matrix-Assisted Laser Desorption/ Ionization mass spectrometry-based approach to evaluate the effects of an LPA1 receptor deficiency on the hippocampal levels of LPA species. Additionally, the impact of stress on the LPA profile was also examined in both wild-type (WT) and the Malaga variant of LPA1-null mice (maLPA1-null mice). Mice lacking LPA1 did not exhibit gross perturbations in the hippocampal LPA species, but the LPA profile was modified, showing an altered relative abundance of 18:0 LPA. Regardless of the genotype, restraint stress produced profound changes in all LPA species examined, revealing that hippocampal LPA species are a key target of stress. Finally, the relationship between the hippocampal levels of LPA species and performance in the elevated plus maze was established. To our knowledge, this study is the first to detect, identify and profile LPA species in the hippocampus of both LPA1-receptor null mice and WT mice at baseline and after acute stress, as well as to link these LPA species with anxiety-like behaviors. In conclusion, the hippocampal LPA species are a key target of stress and may be involved in psychopathological conditions.
Highlights
During the past few decades, studies of factors involved in regulating behavior have rarely focused on the role of lipids
We have characterized the effects of genetic manipulation and exposure to different environmental stresses, such as elevated plus maze (EPM) and restraint stress, on hippocampal levels of LPA species
Lysophosphatidic acid is an important signaling molecule in the brain that is involved in multiple physiological actions and pathophysiological conditions (Fukushima et al, 2001; Tigyi and Parrill, 2003; Aoki, 2004; Ishii et al, 2004)
Summary
During the past few decades, studies of factors involved in regulating behavior have rarely focused on the role of lipids. Advances in lipidomics technology have enabled the precise detection, identification and profiling of lipid species in blood and tissues (Rappley et al, 2009) and have allowed researchers to identify how the lipid composition may influence in behavior (reviewed in Miranda et al, 2019), emotional behavior and stress regulation. Only very few studies have focused on the effects of both acute and chronic stress on the lipid composition or the involvement of lipids in the mechanism regulating mood. Chronic unpredictable stress exposure induces changes in relative cellular levels of both signaling and structural lipids in the brain, including increased phosphatidylcholine (PC) and phosphatidylethanolamine (PE) contents and decreased phosphatidylinositol (PI), phosphatidic acid (PA) and cardiolipin (CL) contents (Faria et al, 2015). A phospholipid hypothesis of depression has been proposed (Horrobin and Bennett, 1999), and lipids are one target of antidepressant treatments (Lee et al, 2009)
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