Protein Degradation, Angelman Syndrome and synaptic plasticity

In addition to new protein synthesis, long-lasting synaptic plasticity also appears to require proper protein degradation by the ubiquitin proteasome system (UPS). For example, we found recently that metabotropic glutamate receptor-dependent LTD (mGluR-LTD) is blocked by UPS inhibitors. Thus, we are interested understanding how neurotransmitter receptors are coupled to the UPS during LTP, LTD, and memory formation in the hippocampus. In particular, we currently are studying the role of two E3 ubiquitin ligases, the anaphase-promoting complex and E6-AP, in LTP, LTD and memory. In addition we have also been looking at Angelman Syndrome and how deletion of UBE3A affects intrinsic neuronal properties and signaling mechanisms with aim of initiating new avenues of therapeutic research.       Right panel: Increase axon initial segment (AIS) length in Angelman Syndrome model mice that lack UBE3A. Left Panel: Ubiquitin-ligase Cdh1 localizes to the PSD in neurons. For examples of our work on this topic, please see: Kaphzan, H., Hernandez, P., Jung, J.I., Cowansage, K.K., Deinhardt, K., Chao, M.V., Abel, T., and Klann, E. (2012) Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors. Biol. Psychiatry, in press. Kaphzan, H., Buffington, S.A., Jung, J.I., Rasband, M.N., and Klann, E. (2011) Alterations in intrinsic membrane properties and the axon initial segment in a mouse model of Angelman syndrome. J. Neurosci. 31: 17637-17648. Li, M., Shin, Y.-H., Hou, L., Huang, X., Wei, Z., Klann, E., and Zhang, P. (2008) The adaptor protein of the anaphase promoting complex Cdh1 is essential role in maintaining replicative lifespan and in learning and memory. Nat. Cell Biol. 10: 1083-1089. Hou, L., Antion, M.D., Hu, D., Spencer, C.M., Paylor, R.E., and Klann, E. (2006) Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51: 441-454.