Fear extinction and acute stress reactivity reveal a role of LPA1 receptor in regulating emotional-like behaviors

LPA₁ receptor is one of the six characterized G protein-coupled receptors (LPA_1–6) through which lysophosphatidic acid acts as an intercellular signaling molecule. It has been proposed that this receptor has a role in controlling anxiety-like behaviors and in the detrimental consequences of stress. Here, we sought to establish the involvement of the LPA₁ receptor in emotional regulation. To this end, we examined fear extinction in LPA₁-null mice, wild-type and LPA₁ antagonist-treated animals. In LPA₁-null mice we also characterized the morphology and GABAergic properties of the amygdala and the medial prefrontal cortex. Furthermore, the expression of c-Fos protein in the amygdala and the medial prefrontal cortex, and the corticosterone response following acute stress were examined in both genotypes. Our data indicated that the absence of the LPA₁ receptor significantly inhibited fear extinction. Treatment of wild-type mice with the LPA₁ antagonist Ki16425 mimicked the behavioral phenotype of LPA₁-null mice, revealing that the LPA₁ receptor was involved in extinction. Immunohistochemistry studies revealed a reduction in the number of neurons, GABA+ cells, calcium-binding proteins and the volume of the amygdala in LPA₁-null mice. Following acute stress, LPA₁-null mice showed increased corticosterone and c-Fos expression in the amygdala. In conclusion, LPA₁ receptor is involved in emotional behaviors and in the anatomical integrity of the corticolimbic circuit, the deregulation of which may be a susceptibility factor for anxiety disorders and a potential therapeutic target for the treatment of these diseases.