Project 3:
How do neurons make connections in the developing brain?
The aim of this research is to understand how neurons become connected to each other to form functional circuits. Many neurological disorders are thought to arise as a result of abnormal connectivity so a fundamental understanding of these developmental mechanisms has the potential to further our knowledge of conditions such as mental retardation, epilepsy and schizophrenia.
Projects are available to investigate the formation of dendrites (branches) and inter-neuronal connections (synapses) in developing neurons and the roles of key molecules (e.g.Seizure-related gene 6 or Sez-6, Wnts, cytokines, Ndfip1) in these important processes.
Sez-6 is a protein that is expressed in the developing brain and in adult neurons in regions important for learning and memory. To investigate the role of Sez-6 we produced a knockout mouse in which the Sez-6 gene was inactivated. Analyses of neurons in the cortex revealed that the dendrites of these neurons were abnormal, that the neurons were less easily excited by electrical stimulation and that there were fewer synapses providing excitatory input to these neurons. Abnormal Sez-6 function may be linked to the development of epileptic seizures and a Sez-6 family member is a candidate gene for autism. Furthermore, the dendrite and synapse abnormalities seen when Sez-6 is lacking are common to a number of mental retardation and neurodegenerative conditions.
Further work is needed to understand the complex molecular pathways regulating the development of neuronal branches and synapses. We use a variety of techniques, including real-time imaging using fluorescent markers of synapses, tissue-specific gene knockout and gene knockdown, to study the roles of different growth and guidance factors in neuronal development.
For more information on projects available, please contact Dr Jenny Gunnersen e-mail: [email protected]
Publications
1. Gunnersen, J.G., Kim, M.H., Fuller, S.J., De Silva, M., Britto, J.M., Hammond, V.E., Davies, P.J., Petrou, S., Faber, E.S.L., Sah, P., Tan, S-S. (2007) Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons. Neuron 56:621-639
2. Gunnersen, J.M., Kuek, A., Phipps, J.A., Hammond, V.E., Puthussery, T. , Fletcher, E. and Tan, S-S (2009) Seizure-Related Gene 6 (Sez-6) in amacrine cells of the rodent Retina and the consequence of gene deletion. PLoS ONE 4(8):e6546
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