The role of urokinase plasminogen activator receptor (uPAR) on forebrain GABAergic interneuron development

Abstract

Although GABAergic interneurons are only a small portion of neurons in the cerebral cortex, they have powerful influence on excitatory neurons and the overall function of neural networks. The disruption of GABAergic interneuron development causes an imbalance between excitation and inhibition and, consequently, a perturbation in overall circuitry. It has been reported that altered interneuron development causes a number of neurological disorders including epilepsy. Studies about the molecular mechanisms involved in GABAergic interneurons development are important to understand the mechanisms underlying neurological disorders. When the urokinase type plasminogen activator receptor (uPAR, gene symbol: Plaur) is genetically eliminated, migration of GABAergic interneurons is altered embryonically. This defect has been attributed to the reduction of hepatocyte growth factor/scatter factor (HGF/SF) levels. In the adult, lack of uPAR causes the reduction of GABAergic interneurons in cerebral cortex and consequently, increased seizure susceptibility and enhanced anxiety. Here I investigate the role of uPAR on postnatal GABAergic interneurons and if the GABAergic interneuron defects in the absence of Plaur can be rescued by postnatal supplementation of HGF/SF. Loss of uPAR alters HGF/SF levels and affects cell proliferation, maturation, and survival during postnatal GABAergic interneuron development in the somatosensory cortex. The defects of GABAergic interneurons are also found in rostral part of forebrain, including the striatum and frontal cortical areas. Postnatal supplementation of HGF/SF can recover some of the GABAergic interneuron development defects, and GABAergic interneurons appear to be properly functional. My thesis work suggests that uPAR regulates postnatal GABAergic interneuron development in the forebrain as a regulator of HGF/SF levels. This molecular mechanism is important to develop potential therapeutic methods for epilepsy.