Deletion of Lysophosphatidic Acid Receptor LPA1 Reduces Neurogenesis in the Mouse Dentate Gyrus

Neurogenesis persists in certain regions of the adult brain including the subgranular zone of the hippocampal dentate gyrus wherein its regulation is essential, particularly in relation to learning, stress and modulation of mood. Lysophosphatidic acid (LPA) is an extracellular signaling phospholipid with important neural regulatory properties mediated by specific G protein-coupled receptors, LPA(1-5). LPA(1) is highly expressed in the developing neurogenic ventricular zone wherein it is required for normal embryonic neurogenesis, and, by extension may play a role in adult neurogenesis as well. By means of the analyses of a variant of the original LPA(1)-null mutant mouse, termed the Malaga variant or "maLPA(1)-null," which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA(1) in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA(1) under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA(1)-null mice demonstrated alterations in brain-derived neurotrophic factor and insulin growth factor 1 levels after enrichment and exercise. Morphological analyses of doublecortin positive cells revealed the anomalous prevalence of bipolar cells in the subgranular zone, supporting the operation of LPA(1) signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors.