Moreno-Fernández R D, Pérez-Martín M, Castilla-Ortega E, Rosell Del Valle C, García-Fernández M I, Chun J, Estivill-Torrús G, Rodríguez de Fonseca F, Santín L J, Pedraza C
Departamento de Psicobiología y Metodología de las CC, Facultad de Psicología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.
Transl Psychiatry. 2017 Apr 4;7(4):e1077. doi: 10.1038/tp.2017.24.
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.
焦虑性抑郁是一种常见疾病，具有严重后果且预后不良。然而，这种情绪障碍背后的神经生物学机制仍未得到充分描述。LPA1受体是六种已被鉴定的G蛋白偶联受体（LPA1 - 6）之一，溶血磷脂酸通过这些受体作为细胞内信号分子发挥作用。该受体的缺失会诱发焦虑以及一些与抑郁密切相关的行为和神经生物学变化。在本研究中，我们试图探究LPA1受体在情绪中的作用。我们首先检测了野生型和maLPA1受体基因敲除小鼠的享乐和绝望样行为。由于maLPA1基因敲除小鼠表现出的行为反应，我们评估了类似惊恐的反应。此外，评估c - Fos表达作为功能活性的指标，随后通过区域间相关矩阵建立功能激活的脑图谱。maLPA1基因敲除小鼠表现出快感缺失、激动和应激反应性增加，这些行为与具有焦虑特征的抑郁的精神病理内表型密切相关。此外，不同基因型的功能脑图谱存在差异。maLPA1基因敲除小鼠的边缘系统激活增加，类似于在抑郁患者中观察到的情况。抗抑郁治疗可诱导行为改善和功能脑图谱正常化。最后，基于有效性标准，maLPA1基因敲除小鼠被提议作为焦虑性抑郁的动物模型。在此，我们首次认为已经确定了LPA1受体与焦虑性抑郁之间的可能关系，为这种抑郁亚型未知的神经生物学基础提供了线索，并为探索治疗情绪障碍尤其是焦虑性抑郁亚型的新治疗靶点提供了机会。
