This research will employ two cellular imaging techniques to develop a new method to identify and quantify changes in glutamate synaptic transmission that are related to developmental and psychiatric disorders in a mouse model and to assess the effects of therapies.
Human genetics studies are beginning to uncover many genes that may contribute to neurodevelopmental and psychiatric disorders. The researchers hypothesize that many of these human genetic mutations directly or indirectly lead to changes in synaptic transmission of glutamate in the cortex. To test this hypothesis, they will develop an optical imaging method that can measure the distribution of two major types of receptors that receive glutamate signals from neighboring brain cells as the cells communicate. Then they will monitor the receptors’ functions as glutamate is passed from one cell to another. The imaging technique requires combining two-photon cellular imaging with a new fluorescent labeling technique, in which a certain type of antibody binds to, and turns on, a fluorescent organic dye molecule. Through this process, they will be able to visualize the two types of glutamate receptors in the dendritic spines of brain cells, which receive glutamate signals from their neighboring cells.
They predict that the several mouse models that have been engineered to harbor disease-linked genetic mutations will show changes in the distribution of these two glutamate receptors at the synapses and that these changes can be quantified. Additionally, they predict that they can successfully use this new combined optical imaging technique to screen drugs for their abilities to reverse the observed changes in the distribution of glutamate receptors.
Significance: The new combined optical imaging approach developed in mouse models may reveal how genetically determined changes in glutamate transmission lead to developmental and psychiatric disorders and become a tool for testing therapies designed to reverse these.