期刊
JOURNAL OF NEUROSCIENCE
卷 31, 期 45, 页码 16194-16207出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5877-10.2011
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资金
- National Institutes of Health [NS17660, NS028710, MH609197]
- Gordon and Betty Moore Foundation Center for Integrative Study of Cell Biology
- Howard Hughes Medical Institute
- National Science Foundation [0543651]
- McGrath Foundation
- Broad Fellows in Brain Circuitry program
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [0543651] Funding Source: National Science Foundation
Densin is an abundant scaffold protein in the postsynaptic density (PSD) that forms a high-affinity complex with alpha CaMKII and alpha-actinin. To assess the function of densin, we created a mouse line with a null mutation in the gene encoding it (LRRC7). Homozygous knock-out mice display a wide variety of abnormal behaviors that are often considered endophenotypes of schizophrenia and autism spectrum disorders. At the cellular level, loss of densin results in reduced levels of alpha-actinin in the brain and selective reduction in the localization of mGluR5 and DISC1 in the PSD fraction, whereas the amounts of ionotropic glutamate receptors and other prominent PSD proteins are unchanged. In addition, deletion of densin results in impairment of mGluR- and NMDA receptor-dependent forms of long-term depression, alters the early dynamics of regulation of CaMKII by NMDA-type glutamate receptors, and produces a change in spine morphology. These results indicate that densin influences the function of mGluRs and CaMKII at synapses and contributes to localization of mGluR5 and DISC1 in the PSD fraction. They are consistent with the hypothesis that mutations that disrupt the organization and/or dynamics of postsynaptic signaling complexes in excitatory synapses can cause behavioral endophenotypes of mental illness.
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