Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction
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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.
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In one study, synapses lacking NMDARs had only a small reduction in the synaptic localization of CaMKII, suggesting contributions of other interacting proteins to its synaptic localization.
“in one study (225) synapses lacking NMDARs had only a small reduction in the synaptic localization of CaMKII, suggesting contributions of other interacting proteins to its synaptic localization.”
From Synaptic memory and CaMKII (2023) · cites this paper as [225]
Lrrc7 knockout mice show significantly increased fighting among littermates.
“Lrrc7 KO mice show significantly increased fighting among littermates [26].”
From An integrated analysis of genes and functional pathways for aggression in human and rodent models (2019) · cites this paper as [26]
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Synaptic Signaling in Learning and Memory
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“It should be noted that in one study (225) synapses lacking NMDARs had only a small reduction in the synaptic localization of CaMKII, suggesting contributions of other inter-acting proteins to its synaptic localization.”
BackgroundAn integrated analysis of genes and functional pathways for aggression in human and rodent models
Zhang-James, Y., Fernàndez-Castillo, N., Hess, J. L., Malki, K., Glatt, S. J., Cormand, B., & Faraone, S. V. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0068-7 · Cited by 98 · see citing works
- Authors
- Carlisle, H. J., Luong, T. N., Medina-Marino, A., Schenker, L., Khorosheva, E., Indersmitten, T., Gunapala, K. M., Steele, A. D., O'Dell, T. J., Patterson, P. H., & Kennedy, M. B.
- Affiliations
- California Institute of Technology (US)
- University of California, Los Angeles (US)
- Corresponding author
- Kennedy, Mary B.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-11-09
- Volume
- 31
- Issue
- 45
- Pages
- 16194-16207
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3235477
- OpenAlex
- W2012192811
- Cited by
- 74
- References
- 59
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 7 · 2014: 8 · 2013: 8 · 2012: 5
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- National Science Foundation (0543651)
- Howard Hughes Medical Institute
- Gordon and Betty Moore Foundation
- National Institutes of Health (MH609197)
- National Institute of Mental Health (MH609197, R01MH060919)
- National Institute of Neurological Disorders and Stroke (R01NS028710, R01NS017660, NS-17660, NS028710)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- postsynaptic density, mGluR5, DISC1, CaMKII, alpha-actinin, long-term depression, NMDA receptor, dendritic spine morphology, schizophrenia endophenotype, autism spectrum disorder, excitatory synapses, synaptic scaffolds, knockout mice
- MeSH terms
- Actins, Aggression, Animals, Behavior, Animal, Mental Disorders, Bicuculline, Body Weight, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Exploratory Behavior, Female, Gene Expression Regulation, Genotype, Glial Fibrillary Acidic Protein, Glycine, Hippocampus, Inhibition, Psychological, Male, Membrane Potentials, Memory, Short-Term, Mice, Inbred C57BL, Motor Activity, Mutation, Nerve Tissue Proteins, Neurons, Picrotoxin, Psychomotor Performance, Sialoglycoproteins, Time Factors, Long-Term Potentiation, Receptors, AMPA, Kainic Acid Receptors, Mice, Knockout, Patch-Clamp Techniques, Statistics, Nonparametric, GABA Antagonists, Recognition, Psychology, Long-Term Synaptic Depression, Rotarod Performance Test, Dendritic Spines, Green Fluorescent Proteins, Mice, Muscle Strength, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Post-Synaptic Density, Endophenotypes, GABA-A Receptor Antagonists, In Vitro Techniques
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