Laboratory Head
Yasunori HAYASHI (M.D.,Ph.D.)
How do we store memory of the external world in our brain? The same question can be found in the ancient Greek literature. What is memory? This is one of oldest and most profound question surrounding brain and mind.
In 1973, Bliss and Lømo first demonstrated the synaptic transmission in the hippocampal dentate gyrus can undergo long-term potentiation (LTP). Since their discovery, after more than three decades of experimentation, various lines of evidence link LTP with memory; drugs or genetic manipulation inhibiting LTP also affect memory formation. Memory cannot form in an animal where LTP is maximally induced to saturation. Likewise, an LTP-like enhancement of synaptic transmission accompanies the establishment of memory. These results suggest that LTP and memory formation share molecular mechanisms, and underscores the importance of learning about the molecular mechanisms of LTP in order to understand memory.
Research in the 80s successfully identified various molecules that are involved in LTP. These efforts confirmed glutamate to be a neurotransmitter in the synapse. The major players in LTP, such as NMDA receptor and CaMKII, were also identified. Whole-cell recording, various pharmacological tools, and genetic approaches have emerged since then and are being used to study LTP. In the 90s, research models confused the field as to the site of long-term potentiation; whether the long-term change is "pre" or "post". These studies relied heavily on the statistical analysis of the response amplitude recorded electrophysiologically. Eventually, however, a critical assumption that quantal transmission established in the neuromuscular junction was shown inapplicable to the central synapse. This exposed the limitations of the approaches at that time. A review entitled "Can molecules explain long-term potentiation" by Lichtman and Sanes (2000) well represents the sentiments of the field at that time.
In view of this, we thought that a breakthrough would not be possible without employing novel technologies. We took the initiative to employ novel technologies such GFP, dominant negative forms, viral vectors, slice culture, two-photon microscopy, Fluorescent (or Förster) energy transfer (FRET) into LTP research. We were the first to assemble all these together and bring them into this context.
- Molecular mechanism of hippocampal learning
- April 3, 2009
- Clarification of the function in synapses associated with Shank, one of genes causing autism, suggests that the normal synaptic skeleton is formed by the network structure of two proteins, Shank and Homer
- Hayashi, M.K., Tang, C., Verpelli, C., Narayanan, R., Stearns, M.H., Xu, R.-M., Li, H., Sala, C., Hayashi, Y.:
"The postsynaptic density proteins Homer and Shank form a polymeric network structure."
Cell 137:159-171, 2009 - Okamoto, K.-I., Narayanan, R., Lee, S.-H., Murata, K., Hayashi, Y.:
"The role of CaMKII as an F-actin bundling protein crucial for maintenance of dendritic spine structure."
Proc. Natl. Acad. Sci. 104:6418-6423 (2007) - Futai, K., Kim, KJ., Hashikawa, T., Scheiffele, M., Sheng, M., Hayashi, Y.:
"Retrograde modulation of presynaptic release probability through PSD-95-neuroligin mediated signaling."
Nat. Neurosci. 10:186-195 (2007) - Kim, M. J., Futai, K., Jo, J., Hayashi, Y., Cho, K., and Sheng, M.:
"Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95."
Neuron 56:488-502 (2007) - Hayashi, M.K., Ames, H., and Hayashi, Y.:
"Tetrameric hub structure of postsynaptic scaffolding protein Homer."
J. Neurosci. 26:8492-8501 (2006) - Takao, K., Okamoto, K., Nakagawa, T., Neve, R. L., Nagai, T., Miyawaki, A., Hashikawa, T., Kobayashi, S., and Hayashi, Y.:
"Visualization of synaptic Ca2+/calmodulin-dependent protein kinase II activity in living neurons."
J. Neurosci. 25:3107-3112 (2005) - Li, Z., Okamoto, K., Hayashi, Y., and Sheng, M.:
"The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses."
Cell 119:873-887 (2004) - Okamoto, K., Nagai, T., Miyawaki, A. & Hayashi, Y.:
"Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity"
Nat. Neurosci. 7:1104-1112 (2004) - Nishi, M., Hinds, H., Lu, H. P., Kawata, M., and Hayashi, Y.:
"Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner."
J. Neurosci. 21:RC185 (2001) - Sala, C., Futai, K., Yamamoto, K., Worley, P. F., Hayashi, Y., Sheng, M.:
"Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a."
J. Neurosci. 23:6327-6337 (2001)