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The Journal of Neuroscience, October 6, 2004, 24(40):8862-8872; doi:10.1523/JNEUROSCI.3213-04.2004

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Cellular/Molecular
SynGAP Regulates Spine Formation

Luis E. Vazquez, Hong-Jung Chen, Irina Sokolova, Irene Knuesel, and Mary B. Kennedy

Division of Biology, California Institute of Technology, Pasadena, California 91125

SynGAP is a brain-specific ras GTPase-activating protein that is an abundant component of the signaling complex associated with the NMDA-type glutamate receptor. We generated mutant mice lacking synGAP to study its physiological role. Homozygous mutant mice die in the first few days after birth; however, neurons from mutant embryos can be maintained in culture. Here, we report that spine and synapse formation are accelerated in cultured mutant neurons, and the spines of mature mutant neurons are significantly larger than those of wild type. Clusters of PSD-95 and subunits of AMPA-type and NMDA-type glutamate receptors accumulate in spines of mutant neurons by day 10 in vitro, whereas in wild-type neurons they are still mostly located in dendritic shafts. The frequency and amplitude of miniature EPSCs are larger in mutant neurons at day 10 in vitro, confirming that they have more functional synapses. At day 21 in vitro, the spines of mutant neurons remain significantly larger than those of wild type. The mutant phenotype at day 10 in vitro can be rescued by introduction of recombinant wild-type synGAP on day 9. In contrast, introduction of mutant synGAP with a mutated GAP domain or lacking the terminal domain that binds to PSD-95 does not rescue the mutant phenotype, indicating that both domains play a role in control of spine formation. Thus, the GAP activity of synGAP and its association with PSD-95 are important for normal regulation of spine and synapse formation in hippocampal neurons.

Key words: synaptogenesis; postsynaptic; NMDA; AMPA; PSD-95; synapsin; filopodia; Ras

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Received Feb 6, 2004; revised August 5, 2004; accepted August 24, 2004.

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