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.

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

“…Animal models are essential to elucidate the neurobiology of depression, to test novel neurobiological hypotheses regarding depression-related outcomes, and to enable the identification of new targets for improved and targeted therapy. We have previously proposed the possible participation of the LPA 1 receptor in affective disorder; if dysfunctional, this receptor might induce vulnerability to the development of anxious depression ( Moreno-Fernández et al, 2017 ), a prominent subtype of depression with unknown neurobiological bases and poor treatment responses compared with anxiety or depression alone ( Richards et al, 2016 ). Because the possible participation of the LPA 1 receptor in depression-like disorders has been proposed in a knockout model with a constitutive lifelong lack of this receptor, validation with pharmacological studies is necessary to assess the contribution of the LPA-LPA 1 signalling pathway to mood disorders.…”

“…Recently, our group was the first to identify a possible relationship between the LPA 1 receptor [one of the six characterised G protein-coupled receptors (LPA 1-6 ) through which lysophosphatidic acid (LPA) acts as an intracellular signalling molecule] and a mixed anxiety-depression phenotype, disclosing a possible neurobiological basis of this subtype of depression. Specifically, maLPA 1 -null mice exhibit a phenotype characterised by depressive ( Moreno-Fernandez et al, 2017 ) and anxious features ( Santín et al, 2009 ; Castilla-Ortega et al, 2010 , 2013 ; Pedraza et al, 2014 ; Moreno-Fernández et al, 2017 ). Indeed, based on validity criteria (face, construct and predictive) and accumulating data from studies of animals lacking the LPA 1 receptor, our group has proposed that maLPA 1 -null mice represent an animal model of anxious depression ( Moreno-Fernández et al, 2017 ).…”

“…Specifically, maLPA 1 -null mice exhibit a phenotype characterised by depressive ( Moreno-Fernandez et al, 2017 ) and anxious features ( Santín et al, 2009 ; Castilla-Ortega et al, 2010 , 2013 ; Pedraza et al, 2014 ; Moreno-Fernández et al, 2017 ). Indeed, based on validity criteria (face, construct and predictive) and accumulating data from studies of animals lacking the LPA 1 receptor, our group has proposed that maLPA 1 -null mice represent an animal model of anxious depression ( Moreno-Fernández et al, 2017 ). In this sense, mice with this genotype exhibit abnormal emotional responses ( Pedraza et al, 2014 ), cognitive alterations in hippocampus-dependent tasks ( Castilla Ortega et al, 2011 , 2014 ), anhedonia ( Moreno-Fernández et al, 2017 ), anxiety ( Santín et al, 2009 ), agitation, increased stress reactivity ( Pedraza et al, 2014 ; Moreno-Fernández et al, 2017 ) dysfunctional coping in response to chronic stress ( Castilla-Ortega et al, 2011 ) and fatigability, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxious features ( Moreno-Fernández et al, 2017 ).…”

“…Indeed, based on validity criteria (face, construct and predictive) and accumulating data from studies of animals lacking the LPA 1 receptor, our group has proposed that maLPA 1 -null mice represent an animal model of anxious depression ( Moreno-Fernández et al, 2017 ). In this sense, mice with this genotype exhibit abnormal emotional responses ( Pedraza et al, 2014 ), cognitive alterations in hippocampus-dependent tasks ( Castilla Ortega et al, 2011 , 2014 ), anhedonia ( Moreno-Fernández et al, 2017 ), anxiety ( Santín et al, 2009 ), agitation, increased stress reactivity ( Pedraza et al, 2014 ; Moreno-Fernández et al, 2017 ) dysfunctional coping in response to chronic stress ( Castilla-Ortega et al, 2011 ) and fatigability, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxious features ( Moreno-Fernández et al, 2017 ). Furthermore, from a neurobiological perspective, adult maLPA 1 -null mice exhibit impairments in hippocampal neurogenesis ( Matas-Rico et al, 2008 ), increased endocrine responses to emotional stimuli ( Pedraza et al, 2014 ), hypoactivity and dysregulation of the normal function of the hypothalamic–pituitary–adrenal (HPA) axis after chronic stress ( Castilla-Ortega et al, 2011 ), and dysfunctional changes among the highly interconnected ‘limbic’ regions and functional reorganisation of the brain network ( Moreno-Fernández et al, 2017 ), all of which are factors that have also been strongly correlated with depression ( Boucher et al, 2011 ) and anxiety ( Hakamata et al, 2017 ).…”

“…Furthermore, from a neurobiological perspective, adult maLPA 1 -null mice exhibit impairments in hippocampal neurogenesis ( Matas-Rico et al, 2008 ), increased endocrine responses to emotional stimuli ( Pedraza et al, 2014 ), hypoactivity and dysregulation of the normal function of the hypothalamic–pituitary–adrenal (HPA) axis after chronic stress ( Castilla-Ortega et al, 2011 ), and dysfunctional changes among the highly interconnected ‘limbic’ regions and functional reorganisation of the brain network ( Moreno-Fernández et al, 2017 ), all of which are factors that have also been strongly correlated with depression ( Boucher et al, 2011 ) and anxiety ( Hakamata et al, 2017 ). Moreover, both the behavioural symptoms and the abnormal patterns of brain connectivity in maLPA 1 -null mice are normalised by antidepressant treatment ( Moreno-Fernández et al, 2017 ).…”