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Published November 9, 2011 | Published
Journal Article Open

Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction


Densin is an abundant scaffold protein in the postsynaptic density (PSD) that forms a high-affinity complex with αCaMKII and α-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 α-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.

Additional Information

© 2011 The Authors. Received November 8, 2010. Revision received July 29, 2011. Accepted August 15, 2011. This research was supported by National Institutes of Health Grants NS17660 and NS028710 (M.B.K.) and MH609197 (T.J.O.), the Gordon and Betty Moore Foundation Center for Integrative Study of Cell Biology (M.B.K. and H.J.C.), the Howard Hughes Medical Institute (A.M.-M.), National Science Foundation Grant 0543651 (T.J.O.), the McGrath Foundation (P.H.P.), and the Broad Fellows in Brain Circuitry program (K.M.G. and A.D.S.). We thank J. Sanes (Harvard University, Boston,MA)and P. Seeburg (Max Plank Institute for Medical Research, Munich, Germany) for mutant mouse strains and Sarah Cantor for help with experiments. Author contributions: H.J.C., T.N.L., A.M.-M., E.K., T.I., K.M.G., A.D.S., T.J.O., P.H.P., and M.B.K. designed research; H.J.C., T.N.L., A.M.-M., L.S., E.K., T.I., K.M.G., and T.J.O. performed research; H.J.C., T.L., A.M.-M., L.S., E.K., T.I., K.M.G., A.D.S., T.J.O., P.H.P., and M.B.K. analyzed data; H.J.C., T.N.L., A.M.-M., A.D.S., T.J.O., P.H.P., and M.B.K. wrote the paper. H.J.C., T.N.L., and A.M.-.M. contributed equally to this work.

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August 19, 2023
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