Fig. 5. Proposed mechanism for LPAR signaling in postnatal hydrocephalus.

Following a severe hemorrhagic event, LPA is released into the CSF. LPA binds to LPA₁ and LPA₃ receptors on the ependymal cells that line the ventricles, causing GPCR overstimulation. After 6 hours, these signaling events cause the ependymal cells to become apoptotic, resulting in ciliary dysfunction and phagocyte recruitment. LPA exposure produces significant ependymal cell loss after 24 hours. With the lack of cilia-driven flow, CSF builds up in the ventricular space, leading to VM and chronic hydrocephalus. These events can be prevented with the genetic deletion of LPA₁ or LPA₃ or through pharmacological inhibition of LPA₁ with the selective antagonist AM095, demonstrating that this effect occurs through activation of specific LPARs.