Ray Kelleher, Arvind Govindarajan, Hae-Yoon Jung, Hyejin Kang, and Tonegawa have discovered that MAPK knockout mice can’t remember things for more than a few hours. MAPK appears to act on memory by up-regulating a large variety of proteins.
Ray Kelleher, a postdoctoral fellow in Tonegawa’s laboratory and lead author of the study, created mutant mice in which the function of MAPK was selectively inactivated in the adult brain. Intriguingly, he found that these mutant mice were deficient in long-term memory storage. In contrast to normal mice’s ability to remember a behavioral task for weeks, the mutant mice could remember the task for only a few hours. Similarly, the researchers found that synaptic strengthening was also much more short-lived in neurons from the mutant mice than in neurons from normal mice.”
Realizing that the pattern of impairments in mutant mice suggested a problem with the production of new proteins, the researchers then performed an elegant series of experiments that revealed precisely how MAPK translates synaptic stimulation into increased protein synthesis. Based on molecular comparisons of neurons from normal and mutant mice, they found that synaptic stimulation normally activates MAPK, and the activated form of MAPK in turn activates several key components of the protein synthesis machinery. This direct regulation of the protein synthesis machinery helps explain the observation that activation of MAPK enhanced the production of a broad range of neuronal proteins.
“Many people had thought that long-term memory formation involved only boosting the synthesis of a very limited set of proteins,” said Tonegawa. “But to our surprise, this process involves ‘up-regulating’ the synthesis of a very large number of proteins.”
An immediate question that Tonegawa and colleagues are pursuing is how neurons target the newly synthesized proteins to the specific synapses participating in memory formation while not modifying other synapses.
In addition to Tonegawa and Kelleher, the study’s other authors (all in Tonegawa’s lab) are graduate student Arvind Govindarajan and postdoctoral fellows Hae-Yoon Jung and Hyejin Kang.