Although the researchers were surprised by the details they discovered about how Arc hinders the signaling process, they didn't come to the insight with complete naivete.
In other work, Marshall had been studying CN2097, designed by co-author Mark Spaller of Dartmouth College (Spaller synthesized it during earlier tenures at Wayne State University and Brown). The compound, which binds to PSD-95 was predicted to protect neurons under conditions of stroke and in disease states such as multiple sclerosis. With co-senior author Dennis Goebel of Wayne State, Marshall and Spaller found this to be the case. During the course of those studies the Marshall group learned that CN2097 enhanced the action of brain-derived neurotrophic factor (BDNF) which is known to be critically involved in long-term potentiation (LTP), a phenomenon believed by many neuroscientists to underlie learning.
Then, when University of North Carolina professor and former Brown postdoc Ben Philpot, now a leading expert on Angelman syndrome, returned to campus in 2008 to speak about Angelman syndrome, he showed how LTP is notably lacking in mice with the condition. After discussions with Philpot, Marshall and his group decided to test whether CN2097 might restore LTP in Angelman mice.
Early on, Marshall said, the team figured the defect in LTP in Angelman mice effect had to do with BDNF signaling.
"We started studying BDNF signaling in the Angelman syndrome mouse and discovered the signaling was defective, so that really was the breakthrough," he said. "It was completely unexpected. It's a new way of thinking about this disease."
That led to the set of experiments now reported in PLOS Biology, in which the group found that CN2097 essentially protects PSD-95 from interference by Arc, helping to restore BDNF signaling and the formation of stronger synapses. In electrophysiological tests on hippocampal tissue of healthy and Angelman mic
|Contact: David Orenstein|