title: Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.
abstract: 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, California 91105, USA.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Carlisle
authors.forename: Tinh N
authors.initials: TN
authors.lastname: Luong
authors.forename: Andrew
authors.initials: A
authors.lastname: Medina-Marino
authors.forename: Leslie
authors.initials: L
authors.lastname: Schenker
authors.forename: Eugenia
authors.initials: E
authors.lastname: Khorosheva
authors.forename: Tim
authors.initials: T
authors.lastname: Indersmitten
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gunapala
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Steele
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Dell
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
authors.forename: Mary B
authors.initials: MB
authors.lastname: Kennedy
mesh_terms: D000199:Actins / Q000378:metabolism; D000374:Aggression / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001640:Bicuculline / Q000494:pharmacology; D001835:Body Weight / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D017774:Long-Term Potentiation / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008570:Memory, Short-Term / Q000502:physiology; D001523:Mental Disorders / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D057907:Post-Synaptic Density / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology; D045442:Rotarod Performance Test; D012795:Sialoglycoproteins / Q000172:deficiency*; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000199:Actins; D001640:Bicuculline; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D005904:Glial Fibrillary Acidic Protein; D005998:Glycine; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D012795:Sialoglycoproteins; C498794:Disc1 protein, mouse; C504462:Lrrc7 protein, mouse
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