Grant: Project Grant

The appropriate stabilization of nerve cell connections is required for the formation of nerve circuits underlying proper brain function. In neurological diseases like schizophrenia and Alzheimer's disease, nerve cell connection stability is impaired. To exploit this knowledge to develop treatments, we first need to understand the factors that regulate connection stability. Our lab studies a protein called pannexin 1. In addition to its role as a doorway providing access through the nerve cell membrane, pannexin 1 regulates the activity of proteins that control changes in cell structure. We recently discovered that nerve cell pannexin 1 inhibits the stabilization of nerve cell connections. Accordingly, a large decrease in the levels of nerve cell pannexin 1 immediately precedes the peak in formation of nerve cell connections. Here we propose to study how nerve cell pannexin 1 inhibits the stability of nerve cell connections and how pannexin 1 is down-regulated during normal brain development. This proposal tests the predictions that (1) nerve cell pannexin 1 acts as a molecular "brake" preventing the remodelling of structural components of nerve cell connections, and that (2) nearby glial cells called astrocytes send signals to down-regulate nerve cell pannexin 1 to release the brake so that nerve circuits can be established. To do this work we will use male and female mice and a combination of tools to image the structure and function of nerve cell connections, the activity of nerve cells, as well as the circuits and effects on behaviour. The outcomes of this project will enable the development of drugs that will maintain the stability of connections rendered vulnerable by neurological disease.