Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity
Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1-null mi...
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doaj-4403fd2e5f9a464989c57c0b6fd772d62020-11-25T02:00:14ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112018-09-0111910.1242/dmm.035519035519Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activityRomán Darío Moreno-Fernández0Andrea Nieto-Quero1Francisco Javier Gómez-Salas2Jerold Chun3Guillermo Estivill-Torrús4Fernando Rodríguez de Fonseca5Luis Javier Santín6Margarita Pérez-Martín7Carmen Pedraza8 Departamento de Psicobiologia y Metodologia en las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Departamento de Psicobiologia y Metodologia en las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Departamento de Psicobiologia y Metodologia en las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga 29010, Spain Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga 29010, Spain Departamento de Psicobiologia y Metodologia en las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Departamento de Biología Celular, Genética y Fisiología. Facultad de Ciencias. Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Departamento de Psicobiologia y Metodologia en las CC, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga 29071, Spain Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1-null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA1 receptor (Lpar1) can induce compensatory mechanisms that might have resulted in the observed deficits. Therefore, in the present study, we have compared the impact of permanent loss and acute pharmacological inhibition of the LPA1 receptor on despair-like behaviours and on the functional brain map associated with these behaviours, as well as on the degree of functional connectivity among structures. Although the antagonist (intracerebroventricularly administered Ki16425) mimicked some, but not all, effects of genetic deletion of the LPA1 receptor on the results of behavioural tests and engaged different brain circuits, both treatments induced depression-like behaviours with an agitation component that was linked to functional changes in key brain regions involved in the stress response and emotional regulation. In addition, both Ki16425 treatment and LPA1 receptor deletion modified the functional brain maps in a way similar to the changes observed in depressed patients. In summary, the pharmacological and genetic approaches could ultimately assist in dissecting the function of the LPA1 receptor in emotional regulation and brain responses, and a combination of those approaches might provide researchers with an opportunity to develop useful drugs that target the LPA1 receptor as treatments for depression, mainly the anxious subtype. This article has an associated First Person interview with the first author of the paper.http://dmm.biologists.org/content/11/9/dmm035519Animal modelsLPA1 receptorGenetic deletionAntagonistFunctional brain mappingMixed anxiety-depression phenotype |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Román Darío Moreno-Fernández Andrea Nieto-Quero Francisco Javier Gómez-Salas Jerold Chun Guillermo Estivill-Torrús Fernando Rodríguez de Fonseca Luis Javier Santín Margarita Pérez-Martín Carmen Pedraza |
spellingShingle |
Román Darío Moreno-Fernández Andrea Nieto-Quero Francisco Javier Gómez-Salas Jerold Chun Guillermo Estivill-Torrús Fernando Rodríguez de Fonseca Luis Javier Santín Margarita Pérez-Martín Carmen Pedraza Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity Disease Models & Mechanisms Animal models LPA1 receptor Genetic deletion Antagonist Functional brain mapping Mixed anxiety-depression phenotype |
author_facet |
Román Darío Moreno-Fernández Andrea Nieto-Quero Francisco Javier Gómez-Salas Jerold Chun Guillermo Estivill-Torrús Fernando Rodríguez de Fonseca Luis Javier Santín Margarita Pérez-Martín Carmen Pedraza |
author_sort |
Román Darío Moreno-Fernández |
title |
Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity |
title_short |
Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity |
title_full |
Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity |
title_fullStr |
Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity |
title_full_unstemmed |
Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity |
title_sort |
effects of genetic deletion versus pharmacological blockade of the lpa1 receptor on depression-like behaviour and related brain functional activity |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2018-09-01 |
description |
Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1-null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA1 receptor (Lpar1) can induce compensatory mechanisms that might have resulted in the observed deficits. Therefore, in the present study, we have compared the impact of permanent loss and acute pharmacological inhibition of the LPA1 receptor on despair-like behaviours and on the functional brain map associated with these behaviours, as well as on the degree of functional connectivity among structures. Although the antagonist (intracerebroventricularly administered Ki16425) mimicked some, but not all, effects of genetic deletion of the LPA1 receptor on the results of behavioural tests and engaged different brain circuits, both treatments induced depression-like behaviours with an agitation component that was linked to functional changes in key brain regions involved in the stress response and emotional regulation. In addition, both Ki16425 treatment and LPA1 receptor deletion modified the functional brain maps in a way similar to the changes observed in depressed patients. In summary, the pharmacological and genetic approaches could ultimately assist in dissecting the function of the LPA1 receptor in emotional regulation and brain responses, and a combination of those approaches might provide researchers with an opportunity to develop useful drugs that target the LPA1 receptor as treatments for depression, mainly the anxious subtype. This article has an associated First Person interview with the first author of the paper. |
topic |
Animal models LPA1 receptor Genetic deletion Antagonist Functional brain mapping Mixed anxiety-depression phenotype |
url |
http://dmm.biologists.org/content/11/9/dmm035519 |
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