title: maLPA1-null mice as an endophenotype of anxious depression.
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.
authors.affiliation: Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: R D
authors.initials: RD
authors.lastname: Moreno-Fernández
authors.affiliation: Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Martín
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Castilla-Ortega
authors.affiliation: Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rosell Del Valle
authors.affiliation: Departamento de Fisiología y Medicina Deportiva, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: García-Fernández
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chun
authors.affiliation: Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitarios de Málaga, Málaga, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Estivill-Torrús
authors.affiliation: Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: L J
authors.initials: LJ
authors.lastname: Santín
authors.affiliation: Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pedraza
mesh_terms: D059445:Anhedonia / Q000502:physiology; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism; D003863:Depression / Q000378:metabolism*; D058068:Endophenotypes; D016762:Genes, fos / Q000235:genetics; D008032:Limbic System / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000523:psychology*; D023421:Models, Animal; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid