Collaborative Research: Molecular Mechanisms of Astrocyte Neuron Interactions in the Development of Synchronous Activity in Neuronal Networks

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Brain cells are of two types. Neurons are the most well-known; they communicate with each other by generating spikes of electrical activity. The second cell type, glial cells, play a variety of roles that are less well understood. In the awake adult brain, the overall spiking activity of neurons appears random. However, in deep sleep or under anesthesia, the spiking activity pattern becomes synchronized within and between various brain regions. During brain development, this type of synchronous spiking is thought to be necessary for the circuit maturation, and the establishment and maintenance of the functional organization of the brain. The focus of this research is to understand the role of one type of glial cell (astrocytes) in the emergence of synchronous spiking activity patterns in the developing brain. The main hypothesis is that astrocytes play a decisive role in the synchronization of neuronal activity in the brain. Preliminary data has demonstrated that astrocytes are necessary for synchronization of spiking activity; the proposed research will elucidate the molecular pathways within astrocytes that control the synchronization of spiking in surrounding neurons. The results of this research will identify fundamental mechanisms of astrocyte-neuron interactions that shape synchronous activity during brain development. This project is conducted at a Historically Black University, and will immerse minority students in cutting edge neuroscience research, and foster peer-mentoring based on interactions between undergraduate and graduate researchers.Preliminary data using mixed neuron and astrocyte cultures on multi-electrode arrays (MEAs) showed random spiking activity which synchronized over time, in comparison to astrocyte-free neuronal cultures, which only show random activity without synchronization. The main hypothesis of this research is that astrocytic release of glutamate mediated by the mGluR1 G-protein-coupled-receptor (GPCR) pathway mediates the effects of astrocytes on the development of neuronal synchronous activity. A model for the mechanism by which the astrocyte mGluR1 pathway mediates neuronal synchronization will be tested using several different dominant negative constructs. A dominant-negative mGluR1 receptor that blocks downstream signaling will be used to understand this signaling pathway's role in both population synchrony, and in the temporal relationship between calcium oscillations within astrocytes and the development of neuronal synchronous bursts. A dominant-negative SNARE protein Vamp2/Syb2 will be used to block glutamate release from astrocytes. The role of the mGluR1 pathway and mGluR1 mediated glutamate release in the development of synchrony will also be examined in vivo. The strength of this project is the combination of multi-electrode electrophysiology, molecular dissection of the mGluR1 pathway in astrocytes, and computational analyses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.