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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / metabolism
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Aggression / physiology
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Animals
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Behavior, Animal / physiology
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Bicuculline / pharmacology
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Body Weight / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Cells, Cultured
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Dendritic Spines / metabolism
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Disease Models, Animal
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Embryo, Mammalian
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Endophenotypes
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Exploratory Behavior / physiology
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Female
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GABA Antagonists / pharmacology
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GABA-A Receptor Antagonists / pharmacology
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Gene Expression Regulation / genetics*
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Genotype
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Glial Fibrillary Acidic Protein / metabolism
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Glycine / pharmacology
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Green Fluorescent Proteins / genetics
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Hippocampus / cytology
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In Vitro Techniques
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Inhibition, Psychological
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Long-Term Potentiation / genetics
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Long-Term Synaptic Depression / genetics
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Memory, Short-Term / physiology
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Mental Disorders / genetics*
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Mental Disorders / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Motor Activity / genetics
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Muscle Strength / genetics
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / cytology
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Neurons / drug effects
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Patch-Clamp Techniques
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Picrotoxin / pharmacology
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Post-Synaptic Density / metabolism*
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Psychomotor Performance / physiology
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Receptors, AMPA / genetics
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Receptors, Kainic Acid / genetics
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Receptors, Kainic Acid / metabolism*
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Recognition, Psychology / physiology
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Rotarod Performance Test
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Sialoglycoproteins / deficiency*
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Statistics, Nonparametric
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Time Factors
Substances
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Actins
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Disc1 protein, mouse
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GABA Antagonists
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GABA-A Receptor Antagonists
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Glial Fibrillary Acidic Protein
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Gluk1 kainate receptor
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Lrrc7 protein, mouse
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Nerve Tissue Proteins
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Receptors, AMPA
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Receptors, Kainic Acid
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Sialoglycoproteins
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Picrotoxin
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Green Fluorescent Proteins
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Glycine
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glutamate receptor ionotropic, AMPA 1
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Bicuculline