Lysophosphatidic acid (LPA) is a simple phospholipid with extracellular signaling properties mediated by specific G protein-coupled receptors. At least 2 LPA receptors, LPA(1) and LPA(2), are expressed in the developing brain, the former enriched in the neurogenic ventricular zone (VZ), suggesting a normal role in neurogenesis. Despite numerous studies reporting the effects of exogenous LPA using in vitro neural models, the first LPA(1) loss-of-function mutants reported did not show gross cerebral cortical defects in the 50% that survived perinatal demise. Here, we report a role for LPA(1) in cortical neural precursors resulting from analysis of a variant of a previously characterized LPA(1)-null mutant that arose spontaneously during colony expansion. These LPA(1)-null mice, termed maLPA(1), exhibit almost complete perinatal viability and show a reduced VZ, altered neuronal markers, and increased cortical cell death that results in a loss of cortical layer cellularity in adults. These data support LPA(1) function in normal cortical development and suggest that the presence of genetic modifiers of LPA(1) influences cerebral cortical development.

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, LPA1-5. LPA1 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 LPA1-null mutant mouse, termed the Malaga variant or “maLPA1-null,” which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA1 in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA1 under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA1-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 LPA1 signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors.

Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have demonstrated a role for this molecule and its LPA1 receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA1 receptor is involved in behavior. Here we studied the phenotype of maLPA1–null mice, which bear a targeted deletion at the lpa1 locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA1-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor coordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes, and coordinated limb use. At behavioral level, maLPA1-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA1 receptor may play a major role in both spatial memory and response to anxiety-like conditions.

Lysophosphatidic acid (LPA) is a new, intercellular signalling molecule in the brain that has an important role in adult hippocampal plasticity. Mice lacking the LPA1 receptor exhibit motor, emotional and cognitive alterations. However, the potential relationship among these concomitant impairments was unclear. Wild-type and maLPA1-null mice were tested on the hole-board for habituation and spatial learning. MaLPA1-null mice exhibited reduced exploration in a novel context and a defective intersession habituation that also revealed increased anxiety-like behaviour throughout the hole-board testing. In regard to spatial memory, maLPA1 nulls failed to reach the controls’ performance at the end of the reference memory task. Moreover, their defective working memory on the first training day suggested a delayed acquisition of the task’s working memory rule, which is also a long term memory component. The temporal interval between trials and the task’s difficulty may explain some of the deficits found in these mice. Principal components analysis revealed that alterations found in each behavioural dimension were independent. Therefore, exploratory and emotional impairments did not account for the cognitive deficits that may be attributed to maLPA1 nulls’ hippocampal malfunction.

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