Project: A Systems Biological Approach to Elucidate Local Protein Synthesis Code in Plasticity and Memory

Protein synthesis seems to be essential for consolidating changes in synapses associated with various forms of learning and memory (synaptic plasticity). However, at present, the relationships between gene expression, protein synthesis, synaptic maintenance and synaptic plasticity are far from clear. Dissecting these relationships, we believe, demands a novel systems biological approach capable of resolving the repertoire of newly synthesized proteins and their actual sites of synthesis (cell body, dendrite, or spine). Towards this goal, we have assembled a group of experts on the regulation of mRNA translation (Proud), molecular mechanisms underlying synaptic plasticity related to learning and memory (Rosenblum), synaptic plasticity related to long-term potentiation (LTP) and growth factor dependent synaptic plasticity (Bramham), and systems biology of the synapse proteome (Armstrong). We propose a collaborative programme that will examine how synapses modify and maintain their characteristics for long durations, with an emphasis on the roles of protein synthesis in these processes. The experimental strategy is designed to elucidate how minute, dynamic and remote synapses are maintained and modified in response to neural activity patterns. This information may ultimately help to explain how the brain, which is composed of labile, short-lived components, can both retain memories and, at the same time, form new ones. This information is crucial for understanding the molecular events that that lead to human neurological disease when such processes are defective.

Acronym	SynProt
Project Results (after finalisation)	Memories can last an entire lifetime. A series of complex biological processes are thought to underpin the ability to form long-term memories and, despite their obvious importance to us they are only partly understood. Evidence gathered by many groups over the past years suggests that the brain needs to synthesise new molecules (proteins) in order to encode new memory. How and when these proteins are made needs to be tightly controlled so that it occurs in the right place at the right time. To try and understand this process better we assembled our consortium, an international group of researchers each specialising in a related but different piece of the jigsaw puzzle. We combined expertise of the Proud (Southampton, UK), Bramham (Bergen, Norway), and Rosenblum (Haifa, Israel) labs in genetic control of memory and its measurement in living brains; expertise in the proteins thought to trigger memory associations; expertise in the biochemical pathways that regulate the formation of new proteins and the expertise of the Armstrong lab (Edinburgh, UK) in building mathematical models of molecules in the brain. As an interdisciplinary group we were able to achieve more during the research programme than we could have as single groups. The specifics of the research are complex but we were able to apply new analytical methods to the data used by the neuroscience groups in order to bring new understanding to the topic. As an example, in collaboration with the Proud group we looked at one of the most important molecular circuits thought to regulate when new proteins are made when neurons need them for memory formation. There were several alternative ways that this circuit could be formed. Together with them we generated a mathematical model for each of the alternative circuit layouts. We showed that all three circuits were theoretically capable of behaving in a way that matched the available data in the laboratory. However we were able to predict new experiments that would differ depending on the circuit layout. These were then performed and a preferred circuit emerged. This was only possible through the close interaction between the research groups, each taking a very different approach. The new insights and understanding of these mechanisms are general in that they are likely to impact across all animal species. In the longer term we can also now look to see how these mechanisms fit into dysfunction either as a normal effect of cognitive decline with age or in disease. The interdisciplinary approach we used in the study could be applied to many other areas of biology and of course there are many other groups of researchers coming together to achieve similar goals in other topics. While doing this we identified that some of the computational tools that we produced would be of wider interest for researchers. Therefore we packaged them up and made these freely available to other researchers to use in and even adapt for their own research.
Network	ERASysBio+
Call	ERASysBio+-2008-01

Project partner

Number	Name	Role	Country
1	University of Haifa	Coordinator	Israel
2	University of Southampton	Partner	United Kingdom
3	University of Bergen	Observer	Norway
4	University of Edinburgh	Partner	United Kingdom