David F. Meaney
Professor and Chair
Department of Bioengineering
University of Pennsylvania
Mechanoregulation of synaptic neurotransmission
Mechanical forces influence the development, maintenance, and degeneration of the nervous system at many length scales. At the synaptic scale, mechanical forces can play a role in the formation and maintenance of the synapse. One well studied synaptic receptor, the NMDA receptor (NMDAR), is considered important in regulating neuronal survival during disease or after injury. In this talk, we show the NMDA receptor is mechanosensitive, and this mechanosensitivity is a key aspect that underlies the role of the NMDA receptor in traumatic brain injury. The molecular domains of the NMDA receptor controlling mechanosensitivity are identified, and we use this molecular map to study how local synaptic signaling is modified following NMDAR mechanoactivation. Next, we use simulations of synaptic networks to identify how normal neurotransmission is altered following traumatic injury, and use these data to test the effectiveness of targeting NMDAR subpopulations for reducing neuronal death after injury. Consistent with predictions, results show that the most effective therapeutic approach is not a broad spectrum inhibition of the receptor, but a more targeted approach that stimulates synaptically localized receptors while inhibiting receptors localized extrasynaptically.