BACKGROUND 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. ; Formal Correction: Error in Funding Posted by PLoS_ONE_Group on 29 Nov 2011 at 22:27 GMT The complete funding information is: "This work was supported by grants from the Spanish Ministry of Education and Science (MEC SEJ2007-61187, MICINN PSI2010-16160 to LJS), Programme for Stabilization of Researchers and Research Technician and Intensification of Research Activity in the National Health System (I3SNS Programme to GET), the Human Frontier Science Programme (to JC, FRDF), Fund for Health Research, Carlos III Health Institute (FIS 02/1643, FIS PI07/0629, FIS PI10/02514 to GET), Red de Trastornos Adictivos RTA (RD06/001 to FRDF), Andalusian Ministry of Health and of Innovation, Science and Enterprise (CTS065 to GET; CTS433 to FRDF) and the US National Institutes of Health MH051699 and MH01723 (to JC). The author E. Castilla-Ortega has a FPU Grant from the Spanish Ministry of Education (AP-2006-02582). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript." Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; This work was supported by grants from the Spanish Ministry of Education and Science (MEC SEJ2007-61187; to LJS), Programme for Stabilization of Researchers and Research Technician and Intensification of Research Activity in the National Health System (I3SNS Programme; to GET), the Human Frontier Science Programme (to JC, FRDF), Fund for Health Research, Carlos III Health Institute (FIS 02/1643, FIS PI07/0629; to GET), Red de Trastornos Adictivos RTA (RD06/001; to FRDF), Andalusian Ministry of Health and of Innovation, Science and Enterprise (CTS065, to GET, and CTS433 to FRDF) and the National Institutes of Health (USA) MH051699 and MH01723 (to JC). The author E. Castilla-Ortega has a FPU Grant from the Spanish Ministry of Education (AP-2006-02582). ; MH01723/MH/NIMH NIH HHS/United States MH051699/MH/NIMH NIH HHS/United States