Research Areas

We form memory daily. And once you remember something, you can recall it even years later. What is the brain mechanism that allows us to retain memory for a long time?
We are studying the molecular mechanism involved in memory formation. We are especially interested in a part of brain called the hippocampus. An animal or human patient with impairment in the hippocampus cannot form a memory. This is what makes us think that the hippocampus is responsible for formation of a memory.

In 1973, Bliss and Lømo made an interesting observation while they are recording synaptic transmission from rabbit hippocampus. When they gave a transient, high frequency stimulation to the synaptic input fiber, the following transmission was increased over next hours.
This was the first demonstration of plasticity of the synaptic transmission now called long-term potentiation or LTP. Since their discovery, after nearly four decades of experimentation, various lines of evidence link LTP with memory. For example, drugs or genetic manipulation that inhibits LTP also affect memory formation. Memory cannot form in an animal where LTP is maximally induced to saturation level. Finally, 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 involved in LTP. These efforts confirmed glutamate to be a neurotransmitter of the synapse. The major players in LTP, such as NMDA type glutamate receptors and CaMKII, were also identified around this time. Whole-cell recording, various pharmacological tools, and genetic approaches have emerged and are still being used to study LTP. However, in the 90s, the field of research confused as to the site of LTP, whether the long-term change is "pre-" or "post-"synaptic. These studies relied heavily on the statistical analysis of the response amplitude recorded electrophysiologically based on a quantal mechanism of synaptic transmission established in the neuromuscular junction. Eventually, however, a critical interpretation of quantal transmission of 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) 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 an approach of "visualizing" the process of LTP by combining novel technologies such GFP, dominant negative forms, viral vectors, slice culture, two-photon microscopy, and Förster energy transfer (FRET). We were the first to assemble all of these together and use them in the LTP research.

Using these approaches, we found out that the postsynaptic structure is rapidly reorganized both structurally and chemically by LTP induction. This manifests itself as a rapid enlargement of dendritic spine where excitatory synapse resides and is accompanied by an increase in synaptic AMPA type glutamate receptor. This is caused by polymerization of F-actin, which starts within 1 min after LTP induction. Currently, we are focusing on the signal transduction machinery involved in the regulation of actin during LTP. We are especially interested in a protein called cofilin, because we found that it translocates rapidly to the synapse after LTP induction and accumulate at the synapse. In next few years, we hope to clarify the signal transduction machinery leading to the structural modification of dendritic spine.

Research Subject

1. Molecular mechanism of hippocampal learning

Related links

1. RIKEN Brain Science Institute Website_Laboratories Page
2. Individual Website Laboratory Page

Press release

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

RIKEN RESEARCH

May 28, 2010

Wired for sight
Proper maturation of the visual cortex in mice, and possibly humans, depends on a maternal gene

June 05, 2009

Shaping the matrix
A mesh-like structure formed by two synaptic scaffolding proteins controls the shape and protein make-up of the synapse

May 25, 2007

Coordinating connections between neurons(Neurons transmit signals in reverse)
'Reverse signaling' orchestrates synaptic activity