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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: 3.51). 08/2009; 8(8):772-84. DOI: 10.1111/j.1601-183X.2009.00524.x
Source: PubMed

ABSTRACT 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.

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Available from: Guillermo Estivill-Torrús, Aug 31, 2015
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    • "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. "
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    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 · 4.65 Impact Factor
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    • "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]. "
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    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
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    • "The potential reasons of reduced running are numerous and may include motor, emotional, hormonal, neurochemical or circadian alterations, that are frequently found in transgenic mice (Brooks et al., 2012; Lalonde et al., 2012; Novak et al., 2012; Taylor et al., 2010; van den Buuse, 2010). In the case of the LPA 1 -null mice, their dramatic running impairment is likely contributed by motor deficits, because impaired neuromuscular strength, equilibrium and grasping reflexes are described in these mice (Santin et al., 2009), together with a disorganized neuronal architecture in the primary motor cortex (Estivill-Torrus et al., 2008). Nevertheless, considering that the absence of the LPA 1 receptor yields to profound neurodevelopmental deficits (Estivill-Torrus et al., 2008; Pedraza et al., 2013), additional alterations such as in the brain systems responsible of the rewarding effects of exercise cannot be ruled out. "
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    ABSTRACT: This work was aimed to assess whether voluntary exercise rescued behavioral and hippocampal alterations in mice lacking the lysophosphatidic acid LPA1 receptor (LPA1-null mice), studying the potential relationship between the amount of exercise performed and its effects. Normal and LPA1-null mice underwent 23 days of free wheel running and were tested for open-field behavior and adult hippocampal neurogenesis (cell proliferation, immature neurons, cell survival). Running decreased anxiety-like behavior in both genotypes but increased exploration only in the normal mice. While running affected all neurogenesis-related measures in normal mice (especially in the suprapyramidal blade of the dentate gyrus), only a moderate increase in cell survival was found in the mutants. Importantly, the LPA1-nulls showed notably reduced running. Analysis suggested that defective running in the LPA1-null mice could contribute to explain the scarce benefit of the voluntary exercise treatment. On the other hand, a literature review revealed that voluntary exercise is frequently used to modulate behavior and the hippocampus in transgenic mice, but half of the studies did not assess the quantity of running, overlooking any potential running impairments. This study adds evidence to the relevance of the quantity of exercise performed, emphasizing the importance of its assessment in transgenic mice research.
    Neuroscience Research 09/2013; 77(3). DOI:10.1016/j.neures.2013.09.004 · 2.15 Impact Factor
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