LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance. (1st March 2020)

• Record Type: Journal Article
• Authors: Moreno-Fernández, R.D.; Rosell-Valle, C.; Bacq, A.; Zanoletti, O.; Cifuentes, M.; Pérez-Martín, M.; Gavito, A.L.; García-Fernández, M.I.; Estivill-Torrús, G.; Rodríguez de Fonseca, F.; Santín, L.J.; Sandi, C.; Pedraza, C.
• Is Part Of: Neuropharmacology. Volume 164(2020)
• Publication Date: 2020-03-01
• Subjects: Stress -- Depression -- LPA1-Receptor -- Glucocorticoids receptors -- Corticosterone -- Excitatory/inhibitory balance; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107896
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1–6 ) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1- receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour. Highlights: The LPA-LPA1- receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. The continuous delivery of LPA in chronically stressed animals has a very unexpected effect on depressive-like behaviour that opposes the effect of its administration in control environmental conditions. Chronic LPA administration under conditions of chronic stress partly mimicked the phenotype of LPA1 -null mice. Under stress, LPA impaired the excitatory/inhibitory balance in the ventral hippocampus and induced a considerable increase in CORT levels after 15 days of restraint stress.