Departamento de Psicobiología y Metodología de las CC, Universidad de Málaga, Campus de Teatinos, Málaga, Spain.
PLoS One. 2011;6(9):e25522. doi: 10.1371/journal.pone.0025522. Epub 2011 Sep 29.
The lysophosphatidic acid LPA₁ receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA₁ receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory.
METHODOLOGY/PRINCIPAL FINDINGS: Male LPA₁-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice.
CONCLUSIONS/SIGNIFICANCE: These results reveal that the absence of the LPA₁ receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA₁ receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology.
溶血磷脂酸 LPA₁ 受体调节成年海马体的可塑性和神经发生。在这里，我们研究了 LPA₁ 受体缺失是否调节慢性应激对海马体神经发生和空间记忆的有害影响。
方法/主要发现：雄性 LPA₁ 缺失（NULL）和野生型（WT）小鼠被分配到对照或慢性应激条件（21 天束缚，每天 3 小时）。溴脱氧尿苷和内源性标志物的免疫组织化学用于检查海马体细胞增殖、存活、年轻神经元的数量和成熟、海马体结构和海马体中的细胞凋亡。另一组小鼠测量皮质酮水平。最后，通过洞板测试评估空间参考和工作记忆。在对照条件下，NULL 小鼠显示细胞增殖减少、年轻神经元群体缺陷、海马体体积减小和空间记忆缺陷中度。然而，主要结果是慢性应激对 NULL 小鼠的海马体神经发生的损害比 WT 小鼠更严重，表现在细胞增殖、细胞凋亡、年轻神经元的数量和成熟以及颗粒区的体积和神经元密度。只有应激 NULL 小鼠表现出皮质醇减少。此外，在慢性应激的 NULL 小鼠中观察到空间参考记忆巩固的明显缺陷，与应激 WT 小鼠观察到的较小影响形成对比。
结论/意义：这些结果表明，LPA₁ 受体缺失加剧了慢性应激诱导的海马体神经发生及其依赖功能的损伤。因此，LPA₁ 受体途径的调节可能与应激诱导的海马体病理学的治疗有关。
