Behavioral phenotype of maLPA1-null mice: Increased anxiety-like behavior and spatial memory deficits

Departamento de Psicobiologíay Metodología de las CC, Universidad de Málaga, Málaga, Spain.
Genes Brain and Behavior (Impact Factor: 3.66). 08/2009; 8(8):772-84. DOI: 10.1111/j.1601-183X.2009.00524.x
Source: PubMed


Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have shown a role for this molecule and its LPA(1) receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA(1) receptor is involved in behavior. In this study, we studied the phenotype of maLPA(1)-null mice, which bear a targeted deletion at the lpa(1) locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA(1)-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor co-ordination 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 co-ordinated limb use. At behavioral level, maLPA(1)-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 LPA(1) receptor may play a major role in both spatial memory and response to anxiety-like conditions.

Download full-text


Available from: Guillermo Estivill-Torrús,
    • "The animals were kept in their respective experimental housing conditions (EE or standard) until behavioral experiments were carried out and also throughout the whole behavioral testing. Moreover, before starting with the experiment, all the rats were submitted to a neurologic exam to evaluate that they did not have motor coordination problems (Santin et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our study examined how different housing conditions modulated the acquisition of a spatial reference memory task and also, a reversal task in the 4-radial arm water maze (4-RAWM). The animals were randomly assigned to standard or enriched cages, and, as a type of complementary stimulation along with the environmental enrichment (EE), a group of rats also ran 15 min/day in a Rotarod. Elevated-zero maze results allowed us to discard that our exercise training increased anxiety-related behaviors. 4-RAWM results revealed that the non-enriched group had a worse performance during the acquisition and also, during the first trial of each session respect to the enriched groups. Regarding the reversal task, this group made more perseverative errors in the previous platform position. Interestingly, we hardly found differences between the two enriched groups (with and without exercise). We also analysed how the reversal learning, depending on the previous housing condition, modulated the expression of c-Fos positive nuclei in different subdivisions of the medial prefrontal cortex (Cingulate (Cg), Prelimbic (PL) and Infralimbic (IL) cortices) and in the Orbitofrontal (OF) cortex. The enriched groups had higher c-Fos expression in the Cg and OF cortices and lower in the IL cortex respect to the non-enriched animals. In the PL cortex, we did not find significant differences between the groups that performed the reversal task. Therefore, our short EE protocol improved the performance in a spatial memory and a reversal task, whereas the exercise training, combined with the EE, did not produce a greater benefit. This better performance seemed to be related with the specific pattern of c-Fos expression in brain regions involved in cognitive flexibility. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; 307. DOI:10.1016/j.neuroscience.2015.08.038 · 3.36 Impact Factor
  • Source
    • "All rights reserved. in the levels of neurotrophic factors, such as brain-derived neurotrophic factors and insulin-like growth factor 1 (IGF-I) [17] and display increased anxiety-like behavior and spatial memory deficits [18]. Although different lines of evidence indicate that LPA 1 regulates brain development and function, currently there is little information on whether LPA 1 activity is affected by drugs used for the treatment of neuropsychiatric diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Different lines of evidence indicate that the lysophosphatidic acid (LPA) receptor LPA1 is involved in neurogenesis, synaptic plasticity and anxiety-related behaviour, but little is known on whether this receptor can be targeted by neuropsychopharmacological agents. The present study investigated the effects of different antidepressants on LPA1 signaling. We found that in Chinese hamster ovary (CHO)-K1 fibroblasts expressing endogenous LPA1 tricyclic and tetracyclic antidepressants and fluoxetine induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and CREB. This response was antagonized by either LPA1 blockade with Ki16425 and AM966 or knocking down LPA1 with siRNA. Antidepressants induced ERK1/2 phosphorylation in human embryonic kidney (HEK)-293 cells overexpressing LPA1, but not in wild type cells. In PathHunter™ assay measuring receptor-β-arrestin interaction, amitriptyline, mianserin and fluoxetine failed to induce activation of LPA2 and LPA3. stably expressed in CHO-K1 cells. ERK1/2 stimulation by antidepressants and LPA was suppressed by pertussis toxin and inhibition of Src, phosphatidylinositol-3 kinase and insulin-like growth factor-I receptor (IGF-IR) activities. Antidepressants and LPA induced tyrosine phosphorylation of IGF-IR and insulin receptor-substrate-1 through LPA1 and Src. Prolonged exposure of CHO-K1 fibroblasts to either mianserin, mirtazapine or LPA enhanced cell proliferation as indicated by increased [(3)H]-thymidine incorporation and Ki-67 immunofluorescence. This effect was inhibited by blockade of LPA1- and ERK1/2 activity. These data provide evidence that different antidepressants induce LPA1 activation, leading to receptor tyrosine kinase transactivation, stimulation of ERK1/2 signaling and enhanced cell proliferation. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 04/2015; 95(4). DOI:10.1016/j.bcp.2015.04.002 · 5.01 Impact Factor
  • Source
    • "Moreover, the LPA1 receptor activates several intracellular signaling pathways mediated through Rho, Phospholipase C, Ras and Phosphatidylinositol 3-kinase proteins [7], signaling cascades that could regulate the expression of early immediate genes, such as c-Fos [65]–[67], and that have implications for anxiety [68]–[69]. As we previously reported, the involvement of the LPA1 receptor pathway in emotion is also consistent with the emotional alterations present in LPA1-null mice, as revealed through reduced activity in the OFT and increased anxiety-like behavior in the EPM and hole-board tests [27], [29]. Moreover, LPA1-null mice are very sensitive to acute stress, displaying an abnormal elevation of both corticosteroid levels and c-Fos activity in the amygdala [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of lysophosphatidic acid (LPA) in the control of emotional behavior remains to be determined. We analyzed the effects of the central administration of 1-oleoyl-LPA (LPA 18∶1) in rats tested for food consumption and anxiety-like and depression-like behaviors. For this purpose, the elevated plus-maze, open field, Y maze, forced swimming and food intake tests were performed. In addition, c-Fos expression in the dorsal periaqueductal gray matter (DPAG) was also determined. The results revealed that the administration of LPA 18∶1 reduced the time in the open arms of the elevated plus-maze and induced hypolocomotion in the open field, suggesting an anxiogenic-like phenotype. Interestingly, these effects were present following LPA 18∶1 infusion under conditions of novelty but not under habituation conditions. In the forced swimming test, the administration of LPA 18∶1 dose-dependently increased depression-like behavior, as evaluated according to immobility time. LPA treatment induced no effects on feeding. However, the immunohistochemical analysis revealed that LPA 18∶1 increased c-Fos expression in the DPAG. The abundant expression of the LPA1 receptor, one of the main targets for LPA 18∶1, was detected in this brain area, which participates in the control of emotional behavior, using immunocytochemistry. These findings indicate that LPA is a relevant transmitter potentially involved in normal and pathological emotional responses, including anxiety and depression.
    PLoS ONE 01/2014; 9(1):e85348. DOI:10.1371/journal.pone.0085348 · 3.23 Impact Factor
Show more