Knuesel, Irene and Elliott, Abigail and Chen, Hong-Jung and Mansuy, Isabelle M. and Kennedy, Mary B. (2005) A role for synGAP in regulating neuronal apoptosis. European Journal of Neuroscience, 21 (3). pp. 611-621. ISSN 0953-816X http://resolver.caltech.edu/CaltechAUTHORS:20120424-145452150
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The brain-specific Ras/Rap GTPase-activating protein synGAP is a major component of the postsynaptic density at glutamatergic synapses. It is a target for phosphorylation by Ca(2+)/calmodulin-dependent protein kinase II, which up-regulates its GTPase-activating activity. Thus, SynGAP may play an important role in coupling N-methyl-D-aspartate-type glutamate receptor activation to signaling pathways downstream of Ras or Rap. Homozygous deletion of synGAP is lethal within the first few days after birth. Therefore, to study the functions of synGAP, we used the cre/loxP recombination system to produce conditional mice mutants in which gradual loss of synGAP begins at approximately 1 week, and usually becomes maximal by 3 weeks, after birth. The resulting phenotypes fall into two groups. In a small group, the level of synGAP protein is reduced to 20-25% of wild type, and they die at 2-3 weeks of age. In a larger group, the levels remain higher than approximately 40% of wild type, and they survive and remain healthy. In all mutants, however, an abnormally high number of neurons in the hippocampus and cortex undergo apoptosis, as detected by caspase-3 activation. The effect is cell autonomous, occurring only in neuronal types in which the synGAP gene is eliminated. The level of caspase-3 activation in neurons correlates inversely with the level of synGAP protein measured at 2 and 8 weeks after birth, indicating that neuronal apoptosis is enhanced by reduction of synGAP. These data show that synGAP plays a role in regulation of the onset of apoptotic neuronal death.
|Additional Information:||© 2005 Federation of European Neuroscience Societies. Received 8 September 2004, revised 10 November 2004, accepted 15 November 2. Article first published online: 10 Feb. 2005. We thank Shannon O’Dell and Alan Rosenstein for expert technical assistance. We also thank members of the Kennedy laboratory for many helpful discussions. This work was supported by NIH grants NS17660 and NS28710 to M.B.K., and Swiss National Foundation fellowship 823A- 064694 to I.K.|
|Subject Keywords:||caspase-3; Cre; mouse; postsynaptic density; Ras/Rap1|
|Official Citation:||Knuesel, I., Elliott, A., Chen, H.-J., Mansuy, I. M. and Kennedy, M. B. (2005), A role for synGAP in regulating neuronal apoptosis. European Journal of Neuroscience, 21: 611–621. doi: 10.1111/j.1460-9568.2005.03908.x|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Melanie Stefan|
|Deposited On:||24 Apr 2012 22:13|
|Last Modified:||24 Apr 2012 22:13|
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