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.

Effects of the LPA1 Receptor Deficiency and Stress on the Hippocampal LPA Species in Mice

“…These receptors are expressed in the brain and may be involved in emotional behavior, particularly the receptors LPA 1 (Santin et al, 2009; Castilla-Ortega et al, 2011; Pedraza et al, 2014; Moreno-Fernández et al, 2017, 2018a,b); LPA 2 (Schneider et al, 2018); LPA 3 (Uchida et al, 2014; Ueda et al, 2018) and LPA 5 (Callaerts-Vegh et al, 2012; Tsukahara et al, 2018). The involvement on emotional regulation of the LPA 1 receptor, through which lysophosphatidic acid signals, has been the most widely investigated (Santin et al, 2009; Castilla-Ortega et al, 2011; Pedraza et al, 2014; Moreno-Fernández et al, 2017, 2018a,b). LPA species containing both saturated and unsaturated long chain fatty acids (e.g., C16 and C18) are able to activate LPA 1 receptors (Bandoh et al, 2000).…”

“…Among lipids, recent data reveal lysophophatidic acid (LPA) as an important lipid signaling molecule that controls behavior (Santin et al, 2009; Castilla-Ortega et al, 2010, 2014, 2016; Orio et al, 2013; Pedraza et al, 2014; Mirendil et al, 2015; Yamada et al, 2015; Moreno-Fernández et al, 2018a; Ladrón de Guevara-Miranda et al, 2019; Sánchez-Marín et al, 2018). LPA is an endogenous, simple, bioactive phospholipid with several biological functions (Yung et al, 2014).…”

“…Although the participation of the LPA receptors, particularly the LPA 2 (Trimbuch et al, 2009; Schneider et al, 2018), LPA 3 (Uchida et al, 2014; Ueda et al, 2018) and LPA 5 receptors (Callaerts-Vegh et al, 2012; Tsukahara et al, 2018) on behavior regulation may not be ruled out, in the brain, LPA appears to function as a regulatory molecule that mainly signals through the LPA 1 receptor (Choi et al, 2010; Chun et al, 2013). The brain distribution of the LPA 1 receptor in emotion-processing regions and the use of LPA 1 receptor null mice, which provide essential information on the putative function of the LPA in the brain, have revealed a role for the LPA-LPA 1 -receptor pathway in regulating the neurobiological variables involved in affective states (Santin et al, 2009; Castilla-Ortega et al, 2011; Pedraza et al, 2014; Moreno-Fernández et al, 2017, 2018a, b). In fact, animals lacking the LPA 1 receptor exhibit emotional dysregulation, impaired extinction of aversive memories (Pedraza et al, 2014), an anxious phenotype (Santin et al, 2009; Castilla-Ortega et al, 2010; Moreno-Fernández et al, 2017, 2018a), cognitive alterations in hippocampus-dependent tasks (Santin et al, 2009; Castilla-Ortega et al, 2010, 2011) and dysfunctional coping in response to chronic stress (Castilla-Ortega et al, 2011).…”

“…The brain distribution of the LPA 1 receptor in emotion-processing regions and the use of LPA 1 receptor null mice, which provide essential information on the putative function of the LPA in the brain, have revealed a role for the LPA-LPA 1 -receptor pathway in regulating the neurobiological variables involved in affective states (Santin et al, 2009; Castilla-Ortega et al, 2011; Pedraza et al, 2014; Moreno-Fernández et al, 2017, 2018a, b). In fact, animals lacking the LPA 1 receptor exhibit emotional dysregulation, impaired extinction of aversive memories (Pedraza et al, 2014), an anxious phenotype (Santin et al, 2009; Castilla-Ortega et al, 2010; Moreno-Fernández et al, 2017, 2018a), cognitive alterations in hippocampus-dependent tasks (Santin et al, 2009; Castilla-Ortega et al, 2010, 2011) and dysfunctional coping in response to chronic stress (Castilla-Ortega et al, 2011). Thus, recent evidence suggests a role for the LPA 1 receptor in regulating the effects of stress on the hippocampus, and the lack of LPA 1 signaling confers vulnerability to chronic stress, which precipitates hippocampal pathology (Castilla-Ortega et al, 2011; García-Fernández et al, 2012) and exacerbates the stress-induced neuroplastic changes, such as reduced adult neurogenesis, increased apoptosis (Castilla-Ortega et al, 2011) and enhanced oxidative stress (García-Fernández et al, 2012).…”

“…Data from both genetic and pharmacological approaches are convergent and provide evidence supporting the hypothesis that the LPA 1 receptor plays an essential role in regulating emotions and mood. The inactivation of this receptor induces depression-like behaviors with an agitation component and is linked to functional changes in key brain regions involved in the stress response and emotional regulation (Pedraza et al, 2014; Moreno-Fernández et al, 2017, 2018a,b).…”