Control of Astrocyte Morphogenesis and Synaptogenesis by Astrocytic Neuroligins

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Astrocytes are essential for neural circuit assembly and function. Specifically, astrocytes play critical roles in development of synapses though release of soluble synaptogenic molecules as well as through contact- dependent mechanisms with neighboring neurons. Astrocyte-synapse interactions are mediated through the elaborate branching of astrocyte processes, often encompassing tens of thousands of synapses per astrocyte. Recently, the Eroglu lab discovered a novel contact-dependent interaction regulating both development of astrocyte morphology and synaptogenesis. This interaction is mediated through astrocytic neuroligins, a family of cell adhesion molecules previously studied exclusively in neurons. Neuroligins are post-synaptic proteins that make transcellular connections with pre-synaptic neurexins to regulate synaptogenesis and synaptic transmission. Interestingly, the Eroglu lab found that astrocytic neuroligins perform distinct functions from neuronal neuroligins, demonstrating that their expression in astrocytes is functionally significant. Specifically, this study established that loss of astrocytic neuroligin-2 is sufficient to significantly diminish elaboration of astrocyte branching and disrupt the excitation/inhibition balance in the mouse cortex. While these findings highlight a novel player in astrocytic control of morphogenesis and synaptogenesis, the molecular underpinnings of astrocytic neuroligin interactions remain unexplored. Here, I aim to elucidate the molecular mechanisms governing astrocytic neuroligin-2 involvement in astrocyte morphogenesis, synapse development and synaptic physiology. To do so, I will use both in vitro and in vivo manipulation of astrocytic neuroligin-2 to 1) use quantitative proteomics to discover and validate intracellular and extracellular astrocytic neuroligin-2 binding partners critical for regulation of astrocyte morphogenesis and synaptogenesis 2) assess the sufficiency of astrocytic neuroligin-2 to organize post-synaptic membranes and 3) assess synaptic function in astrocytic neuroligin-2 null brains. In summary, the data collected in these studies will reveal how astrocytic neuroligin interactions control development of both astrocytes and synapses and ultimately how these mechanisms converge to influence synaptic transmission. Neuroligins have been implicated in neurodevelopmental diseases such as autism and schizophrenia and therefore, it is imperative to understand the comprehensive functions of neuroligins in all cell types of the brain.