Parent Grant: ?Control of Astrocyte Development and Astrocyte-Synapse Interactions? (1R01NS102237-01A1) Title: Regulation of Astrocyte and Synapse Development via Neuroligin-Neurexin Interactions Neuroligins have been shown to play key roles in neuronal organization of pre- and postsynaptic elements by associating transsynaptically with their partners, the neurexins. There are three neuroligin family members (NL1, NL2 and NL3). At the neuronal synapse, these cell adhesion molecules have been shown to increase the number of synapses as well as functionally alter synaptic transmission. Neuroligins and neurexins have also been implicated in the risk for disorders such as autism and schizophrenia. Recent work from our lab has shown that astrocytes, the primary glial subtype of the brain, express neuroligins as well. Our lab demonstrated that astrocyte neuroligins are required for proper astrocyte morphogenesis and that this process is dependent on neuronal neurexins. The loss of NL2 in astrocytes altered the proper development of synapses indicating a link between proper astrocyte morphology and synapse function. Our goal is to understand the mechanism by which astrocytes attain their morphology in conjunction with the underlying synaptic circuitry. Specifically, we will investigate the mechanisms by which the two other neuroligins (NL1 and NL3) mediate the link between astrocyte and synapse development. Through these studies, we will address the important roles astrocytes play in the etiology of neurodevelopmental disorders, such as autism, in which synaptic pathology is the underlying driver of disease phenotypes. Moreover, we will deepen our mechanistic understanding of cell-cell interactions that control brain development and function. This research will take place at Duke University, under the mentorship of Dr. Cagla Eroglu and Dr. Ji Ru-Rong. Duke University is a leading research institute, with stellar records in graduate training in cell biology and neurobiology. Apart from access to top notch core facilities including transgenic mice, light microscopy and proteomics, there is a strong collaborative culture between the labs that have expertise in glia and synapse biology, which will contribute to the training and success of the candidate Mr. Ramirez. Dr. Eroglu is an expert in glial and neuronal cell biology who is well-established in the fields of synapse formation and neuron-glia interactions. Dr. Ji is renowned in the field of neuro-glia interactions in chronic pain with a particular expertise in electrophysiology. Together, their mentorship will ensure cohesive training required for the success of this project.
Statement: The studies proposed here will investigate how astrocyte expressed neuroligin 1 and 3 mediate astrocyte- synapse interactions across development. An understanding of this mechanism will elucidate the contribution of astrocytes in the development of neurological disorders, such as autism and schizophrenia, that are driven by synaptic dysfunction. This could open the way for new therapies that target astrocyte-synapse interaction to modify disease outcomes.
| Risher, W Christopher; Kim, Namsoo; Koh, Sehwon et al. (2018) Thrombospondin receptor ?2?-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol 217:3747-3765 |
