1. maLPA1-null mice as an endophenotype of anxious depression
- Author
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F. Rodríguez de Fonseca, Carmen Pedraza, María García-Fernández, Luis J. Santín, Margarita Pérez-Martín, Román D. Moreno-Fernández, C Rosell del Valle, Guillermo Estivill-Torrús, Jerold Chun, Estela Castilla-Ortega, [Moreno-Fernández ,RD, Rosell del Valle,C, Santín,LJ, Pedraza,C] Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Pérez-Martín,M] Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Castilla-Ortega,E, Rodríguez de Fonseca,F] Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain. [García-Fernández,MI] Departamento de Fisiología y Medicina Deportiva, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Chun,J] Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. [Estivill-Torrús,G] Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitarios de Málaga, Málaga, Spain., This research was funded by the Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863 to CP and CTS-643 to GE-T) and of Health (Nicolas Monardes programme, to GE-T), and the Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to LJS and CP). Author EC-O. holds a Sara Borrell’ research contract from the National System of Health, ISC-III (Grant Number: CD12/00455). Author RDM-F holds a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610). Author CRdV holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment (FPDI 2010).
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0301 basic medicine ,Male ,Anhedonia ,Ratones ,Trastornos del humor ,Anxiety ,Brain mapping ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic Acid [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Mice ,0302 clinical medicine ,Depresión ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Limbic System ,Endofenotipos ,Psychiatry and Psychology::Behavior and Behavior Mechanisms::Neurobehavioral Manifestations::Anhedonia [Medical Subject Headings] ,Receptors, Lysophosphatidic Acid ,Phenomena and Processes::Genetic Phenomena::Phenotype::Endophenotypes [Medical Subject Headings] ,Mice, Knockout ,Depression ,Pronóstico ,Brain ,Genes, fos ,Humanos ,Pánico ,Psychiatry and Mental health ,Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Fear::Panic [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [Medical Subject Headings] ,Schizophrenia ,Encéfalo ,Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::Lysophospholipids [Medical Subject Headings] ,Models, Animal ,Antidepressant ,Original Article ,Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings] ,medicine.symptom ,Psychology ,Ratones noqueados ,medicine.medical_specialty ,Endophenotypes ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Psychotropic Drugs::Antidepressive Agents [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal [Medical Subject Headings] ,Lisofosfolípidos ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Ansiedad ,medicine ,Animals ,Antidepresivos ,Psychiatry ,Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Anxiety [Medical Subject Headings] ,Biological Psychiatry ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Modelos animales ,Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings] ,medicine.disease ,Psychiatry and Psychology::Mental Disorders::Mood Disorders [Medical Subject Headings] ,030104 developmental biology ,Mood ,Mood disorders ,Endophenotype ,Animales ,Receptores del ácido lisofosfatídico ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings] ,Lysophospholipids ,Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::Depression [Medical Subject Headings] ,Neuroscience ,Genotipo ,030217 neurology & neurosurgery ,Stress, Psychological - Abstract
Anxious 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.
- Published
- 2016