Grant: Operating Grant

Brain cells require precise communication in space and time in order to orchestrate movements and thinking. Communication between these cells occurs at highly specialized points of contact called synapses, at which an electrical signal in one brain cell is converted to a chemical signal which is sensed by receptors on the next cell in the circuit. One key receptor in the brain is called the "NMDA" receptor, which mediates mechanisms underlying learning and memory ("synaptic plasiticity"); however, when over-activated, NMDA receptors can signal cell death. Recent studies show that NMDA receptors located in synapses are beneficial, signaling cell survival and contributing to learning, whereas NMDA receptors residing outside synapses predominantly signal cell stress or death. Previous work suggests these receptors are upregulated on the surface of brain cells and show increased numbers outside synapses in the hereditary disorder Huntington disease (HD). HD is caused by a mutation in the gene coding for the protein huntingtin, and is associated with selective loss of brain cells with onset in mid-life, resulting in abnormalities of movement, mood and memory. The proposed study will investigate the mechanisms underlying altered location of NMDA receptors, and the consequences to brain cell signaling such as synaptic plasticity and cell death pathways, in a mouse model of Huntington disease.