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O'Shea Lab

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Our Research

Mechanisms of synaptic pruning

We are broadly interested in how interactions between glia and neurons may alter neuronal function in normal and diseased conditions. Our ongoing project aims to understand how glial cells specifically eliminate excessive and weak synapses to form mature neuronal circuits during a postnatal developmental process known as synaptic pruning. Previous studies have established that microglia and astrocytes both engulf synaptic components during synapse pruning. Microglia utilize complement receptors to recognize complement coated weak synapses, while astrocytes employ two phagocytic receptors (MERTK and MEGF10) to recognize weak synapses. However, it is not known what molecular cues recruit complement proteins and astrocyte phagocytic receptors to synapses; it is also not understood how weak synaptic activity triggers the display of such molecular cues at synapses. Combining in vivo assays and in vitro co-culture models, we aim to identify the molecular cues that mark weak synapses for glia-mediated elimination and elucidate the molecular mechanisms that translate weak synaptic activity to the display of such cues. 

iPSC models of Parkinson’s Disease:

Current work focuses on understanding the misregulation of cell-type specific functions in neurodegenerative disorders such as Parkinson’s disease (PD). Using directed differentiation of patient-derived induced pluripotent stem cells (iPSCs), we model complex interactions between dopaminergic neurons, astrocytes and microglia carrying PD-related mutations. By employing cutting-edge microscopy techniques, we study how PD-related mutations affect organelle function and dynamics, as well as overall neuronal physiology. Furthermore, we use sequencing-based approaches to characterize the cell-type specific regulation of gene expression in PD, with the goal of identifying gene regulatory mechanisms that contribute to cellular malfunction in PD.

Dissecting the activity-dependent regulation of synaptic receptors:

We are also interested in how activity-dependent regulation of neurotransmitter receptors modulates synaptic plasticity. We have used CRISPR/Cas9 techniques to tag endogenous receptors in primary cultured neurons. We plan to use single particle tracking and other advanced microscopy techniques to examine the trafficking and recycling properties of endogenous receptors at synapses. Moreover, we will examine how changes in the subunit composition of these receptors also contributes to synaptic plasticity.