Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity

Abstract

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.

Keywords

• Animal models
• LPA1 receptor
• Genetic deletion
• Antagonist
• Functional brain mapping
• Mixed anxiety-depression phenotype