Title: novel routes to the activation of gene transcription by synaptic activity: Brain cells (neurons) communicate with each other by releasing chemical messengers (neurotransmitters) onto each other at structures called synapses, a process called 'synaptic activity'. These messengers are detected by special channels on the cell surface, which then open and allows calcium and sodium ions to flow into the cell. This triggers the release of neurotransmitter onto yet more neurons. This means of neuron-to-neuron communication is the way by which information flows round the brain. However, 'synaptic activity' also triggers changes inside neurons. The calcium ions which flow into the neuron activate signal pathways, which in turn activate the transcription of genes. Transcription is a crucial step in the process whereby genes (made of DNA and located in the nucleus) are read by the cell's machinery and decoded into new proteins. These new proteins are crucial for many fundamental processes in the neuron. For example, learning and memory involves changes in the way neurons communicate with each other, and this process relies on these new proteins made in response to 'synaptic activity'. These new proteins also control how neurons in the brain develop from the foetus, through infancy and on to adulthood. Equally importantly, these new proteins also make individual neurons healthier and more likely to survive for longer than neurons that don't experience synaptic activity. Therefore, an understanding of how synaptic activity activates gene transcription is an important problem for scientists studying the brain. Our proposed research will characterise a completely new way by which genes can be activated by synaptic activity. The transcription of many genes is suppressed by special molecules called corepressors. One particularly important one is called SMRT, which represses many different genes in the nucleus by blocking the action of the cell's transcription machinery. We have recently discovered that when calcium ions flow into neurons following synaptic activity, signals in the neuron are activated which cause SMRT to leave the nucleus and go into the cytoplasm. Once in the cytoplasm, SMRT is unable to suppress transcription because the genes and transcription machinery are all in the nucleus. Therefore these genes become much easier to activate. Our work will uncover the exact signalling events that take place that make SMRT stop repressing transcription in the nucleus, and go into the cytoplasm. In addition, we will identify exactly what type of genes are likely to be influenced by this 'export' of SMRT. We will also determine the effect that SMRT export has on the way in which a neuron develops, looking particularly at the way a neuron changes shape as it matures. Because SMRT is known to repress the transcription of so many types of gene, signals that stop SMRT from working have the potential to have a big effect on the neuron. As mentioned earlier, the activation of gene transcription by synaptic activity controls many very important processes. SMRT export triggered by synaptic activity is a previously undiscovered route by which transcription of many genes can be turned on. Therefore understanding the mechanism and consequences of this process is of utmost importance. While this work is centred on the study of neurons, SMRT represses genes in many cell types, so the relevance of this work is not restricted to neurons. Furthermore, calcium ions don't just have effects in neurons, they are able to activate signalling pathways in all types of cell, from white blood cells to egg cells. The gene transcription that calcium ions activate in these cells are important for other processes, such as for white blood cells to fight infection. therefore our discoveries regarding how calcium activates gene transcription in neurons will be of benefit to scientists researching a wide variety of problems.