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: 3.6). 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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    ABSTRACT: Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator with diverse biological properties. We previously found altered expression of the LPA-related genes in rodents after treatment with sertraline, which is widely used to treat anxiety disorders and depression. However, little is known about the behavioral effects of LPA. In the present study, we investigated the behavioral effects of intracerebroventricular injection of LPA in adult mice. LPA did not significantly affect spontaneous locomotor activity, suggesting that LPA does not induce hyperactivity, ataxia, or sedation. We next investigated the emotional effects of LPA via the hole-board test. LPA significantly increased the number of head-dips in a dose- and time-related manner. A significant induction of head-dip counts occurred 15 and 30 min after LPA administration. To clarify the involvement of LPA receptors, we examined the effect of the non-selective LPA1-4 receptor antagonist, 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA) co-administered with LPA. BrP-LPA dose-dependently inhibited LPA-induced head-dip counts. We next investigated anxiety-like behavior via the elevated plus-maze test. LPA significantly reduced the percentage of time spent in the open arms and BrP-LPA dose-dependently inhibited this anxiety-like behavior. In conclusion, LPA induced anxiety-like behavior in mice via LPA receptors. Our results suggest that LPA signaling plays an important role in regulating anxiety in mice.
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    ABSTRACT: Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signaling properties are mediated by 7-transmembrane, G protein-coupled receptors (GPCRs), constituent members of which have continued to be identified after their initial discovery in the mid-1990s. Here we briefly review this class of receptors, with a particular emphasis on their protein and gene nomenclatures that reflect their cognate ligands. There are six lysophospholipid receptors that interact with lysophosphatidic acid (LPA): protein names LPA1 – LPA6, and italicized gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human). There are five sphingosine 1-phosphate (S1P) receptors: protein names S1P1-S1P5, with gene names S1PR1-S1PR5 (human), S1pr1-S1pr5 (non-human). Recent additions to the lysophospholipid receptor family have resulted in the proposed names for a lysophosphatidyl inositol receptor: protein name LPI1, gene name LPIR1 (human) and Lpir1 (non-human); and three lysophosphatidyl serine receptors: protein names LyPS1, LyPS2, LyPS3 and gene names LYPSR1-LYPSR3 (human) and Lypsr1-Lypsr3 (non-human); a variant form that does not appear to exist in humans is provisionally named LyPS2L, without a name recommendation for its mouse-specific gene. This nomenclature incorporates prior recommendations from International Union of Basic and Clinical Pharmacology (IUPHAR), Human Genome Organization (HUGO) gene nomenclature committee (HGNC), and Mouse Genome Informatix (MGI).
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    ABSTRACT: Lysophosphatidic acid (LPA) is an endogenous phospholipid which is involved in many different cellular processes through specific G-protein coupled receptors (LPA1-6). The finding of a lysophosphatidic acid (LPA) signaling pathway in the developing and adult brain led to the characterization of the functional roles of LPA in normal and diseased brain. Previous studies using pharmacological or genetic approaches such as receptor null mice have been demonstrated as indispensable to determine the requirement of, at least, LPA1 receptor for normal brain function and its influence in many different processes including neural cell proliferation and differentiation, cell survival, synapsis, neural transmission, or neurochemical balance in a variety of cerebral areas although, remarkably, the hippocampus. To date numerous contributions have showed behavioral alterations affecting cognition and emotional behavior in correlation with structural and neurochemical observations. Here we review the functions of LPA in behavior, principally particularized to those mediated by LPA1 receptor, and also discuss their relevance to psychiatric disorders.
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