Lysophosphatidic Acid Signalling in Nervous System Development and Function

Abstract

One class of molecules that are now coming to be recognized as essential for our understanding of the nervous system are the lysophospholipids. One of the major signaling lysophospholipids is lysophosphatidic acid, also known as LPA. LPA activates a variety of G protein-coupled receptors (GPCRs) leading to a multitude of physiological responses. In this review, I describe our current understanding of the role of LPA and LPA receptor signaling in the development and function of the nervous system, especially the central nervous system (CNS). In addition, I highlight how aberrant LPA receptor signaling may underlie neuropathological conditions, with important clinical application.

Keywords: Autotaxin; Axon guidance; Cortical development; LPA receptors; Lysophospholipid; Neuropathic pain.

Fig. 1

Neurodevelopmental roles of LPA. Various aspects of CNS development are likely to be involved in LPA signaling through LPA receptors. a) Based on autotaxin genetic null mice, LPA signaling is required for cranial neural tube closure. This involves multiple LPA receptors, with no specific LPA receptor null mice recapitulating this phenotype. Additionally, regionalization of the neural tube at the midbrain/hindbrain border requires LPA, but again the receptors have not yet been identified. b) Various experiments demonstrate that LPA signaling through LPA₁ and LPA₂ are involved in cortical layer formation. Initial studies suggest that LPA₁ is important for neuroprogenitor survival in the ventricular zone (VZ) and LPA₂ later in their differentiation. Furthermore, LPA₄ may also be involved in the migration of early cortical neurons to the layers of the cortical plate. c) LPA has properties suggesting it could be guiding axons to their correct targets during development. LPA is repulsive to axonal growth cones and can cause them to collapse through a G_12/13-Rho-ROCK pathway. However, the LPA receptors mediating these growth cone responses have not been elucidated. d) Studies from genetic null mice, especially Lpar1 null animals, indicates a role for LPA in proper synaptic transmission, especially for glutamatergic synapses, and that could be developmental in origin. Lpar1 null mice show changes in glutamate, serotonin and GABA and a deficit in prepulse inhibition. Hippocampal CA1 pyramidal cells have more immature dendritic spines and reduced MMP-9 in Lpar1 null mice. LPA and LPA₁ appear to be involved both presynaptically and postsynaptically.

Fig. 2

Model for the role of LPA in neuropathic pain. In a, the initiation events leading to LPA production are described, while b summarizes the responses to LPA and involvement of LPA in maintenance of the neuropathic pain response. Neuropathic pain development is thought to be initiated by an intense pain response that results in both Aδ fibers releasing glutamate (Glu) to activate NMDA receptors (NMDAR) and C fibers releasing Substance P (SP) to activate Neurokinin-1 (NK-1) receptors in the spinal cord. This may lead to activation of cytosolic phospholipase A(2), cPLA2, and calcium-independent phospholipase A(2), iPLA2, to catalyze the production of lysophosphatidylcholine (LPC) extracellularly which is converted to LPA by autotaxin (ATX) in the CSF. This LPA may bind to microglia, either through LPA₁ or LPA₃ receptors, which activate the microglia for a feed-forward production of additional LPA, possibly through microglial secretion of Interleukin-1β (IL-1β). In addition, LPA is transported to the dorsal root where it binds to LPA receptors on Schwann cells. As noted in b, LPA activation of Schwann cells causes demyelination in the dorsal root. Furthermore, the α₂δ₁ subunit of the voltage-gated calcium channel is upregulated in the dorsal root as well as protein kinase C γ-isoform (PKCγ) in the spinal cord. There is proposed to be cross-talk between Aβ and Aδ fibers that result in the severe pain response to innocuous stimuli; in addition, possible sprouting of Aβ and Aδ fibers in the spinal cord could lead to more intense stimulation. Furthermore, there is evidence of the involvement of LPA₅ as well as astrocytes and microglia late in the maintenance of the neuropathic pain state. Finally, note that although this model is based on experimental evidence, some aspects, such as cellular locations of LPA receptors, have not been precisely determined yet.