UC San Diego

Hypoxic insult during early pregnancy can give rise to neuronal disorders of the newborn, such as autism, schizophrenia and epilepsy. Of these disorders, the underlying similarity is cortical dysplasia, in which the neuronal layers are disrupted due to abnormal neuronal migration. The infliction of hypoxia during the critical period of neuronal development and migration can cause abnormalities which can propagate into these migration defects observed after birth. The purpose of this dissertation is to investigate the effect of hypoxia on early neuronal development, and the role of lysophosphatidic acid receptor-1 (LPA₁) in this pathological process. LPA₁ is one of 6 G-protein-coupled- receptors (GPCRs) which are activated by a bioactive lipid, LPA. It is highly enriched in the ventricular zone of the cortex during development, suggesting its importance in neural progenitor cells (NPCs). Previously, LPA treatment of ex vivo cortices at embryonic age 13.5, a period of neurogenesis and early neuronal migration, was reported to induce ectopic displacement of mitotic NPCs. Strikingly, in this study, a similar displacement of mitotic NPCs, together with delayed early post-mitotic neuronal migration and N-cadherin disruption, was observed in cortices exposed to hypoxia, which was obliterated in LPA₁ null cortices. This indicates that LPA₁ is an essential mediator of hypoxia in the developing cortex. Through the use of pharmacological inhibitors, it was demonstrated that hypoxia signals through LPA₁ through Gi and subsequent downstream effectors. Importantly, a novel mechanism of how hypoxia activates LPA₁ was discovered: Hypoxia inhibits GRK2, a GPCR kinase which associates with LPA₁ to cause sequestration, hence promoting LPA₁ activity. LPA signaling has been implicated in various stages of vascular development, but blood vessel integrity in these receptor knockout mice have not been investigated in depth. In a separate study, it was observed that LPA₁/ LPA₂ double null mice exhibit an increased blood vessel leakage and blood vessel density specifically in the cortex during the period around birth persisting into early postnatal life. Also, these cortical endothelial cells appear to be unhealthy and electron-light. These striking phenotypes could shed light on the role of LPA signaling in blood brain barrier formation in the brain