Moreno-Fernández, R DPérez-Martín, MCastilla-Ortega, ERosell Del Valle, CGarcía-Fernández, M IChun, JEstivill-Torrús, GRodríguez de Fonseca, FSantín, L JPedraza, C2017-05-262017-05-262017-04-04Moreno-Fernández RD, Pérez-Martín M, Castilla-Ortega E, Rosell del Valle C, García-Fernández MI, Chun J, et al. maLPA1-null mice as an endophenotype of anxious depression. Transl Psychiatry. 2017;7(4):e1077.http://hdl.handle.net/10668/2670Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.enAnimalesAntidepresivosAnsiedadEncéfaloDepresiónEndofenotiposGenotipoHumanosLisofosfolípidosRatonesRatones noqueadosModelos animalesTrastornos del humorPánicoPronósticoReceptores del ácido lisofosfatídicoMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Neurobehavioral Manifestations::AnhedoniaMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Psychotropic Drugs::Antidepressive AgentsMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::AnxietyMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::DepressionMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype::EndophenotypesMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::GenotypeMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::LysophospholipidsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, KnockoutMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, AnimalMedical Subject Headings::Psychiatry and Psychology::Mental Disorders::Mood DisordersMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Fear::PanicMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::PrognosisMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic Acidresearch article28375206open access10.1038/tp.2017.242158-3188PMC5416683