Fear extinction and acute stress reactivity reveal a role of LPA1 receptor in regulating emotional-like behaviors
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LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1–6) 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.
KeywordsLysophosphatidic acid Fear extinction Acute stress reactivity Amygdala Prefrontal cortex GABA
We are grateful to Juan Gómez Repiso for his technical assistance, Elisa Matas-Rico for her contribution to the NeuN and calcium-binding proteins immunohistochemistry, Román Moreno and Marina Navarro for their contribution to stereological quantification of GABA+ cells, Jose Peral for his help in the pharmacological experiment, and Jose Ángel Aguirre Gómez for access to stereology. We thank the animal housing facilities of the University of Málaga for maintenance of the mice. This work was supported by grants from Spanish Ministry of Economy and Competitiveness (MEC SEJ2007-61187, co-funded by ERDF, MICINN PSI2010-16160, to L.J.S.; PI10/02514, co-funded by ERDF, to G.E-T; Red de Trastornos Adictivos RD06/001/0000, to F.R.F), Andalusian Ministries of Health and Economy, Innovation, Science and Employment (SEJ-4515, to L.J.S; CTS643 and Nicolás Monardes Programme, to G.E-T.; and SAF2010-20521, to F.R.F). E.C., J.S. and E.Z. were supported by an FPU Grant of the Spanish Ministry of Education (AP-2006-02582, AP-2007-03719, and AP-2010-2044, respectively) and University of Malaga (Ayuda para la actividad productiva del PIF, III Plan Propio) and Postdoctoral Fellowship ‘Sara Borrell’ of the National Institute of Health Carlos III to E.C.C.R. was supported by a FPU Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment (FPDI 2010).
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