Journal
JOURNAL OF NEUROSCIENCE
Volume 38, Issue 1, Pages 200-219Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0936-17.2017
Keywords
behavior; chemokine; CTCF; dendritic spine; inflammation; microglia
Categories
Funding
- National Institutes of Health (NIH Neurological Sciences Academic Development Grants) [K12NS001690, T32NS007205, RO1AG013730, RO1NS087632]
- National Cancer Institute Cancer Center Support Grant [NCI P30CA91842]
- Institute of Clinical and Translational Sciences/Clinical and Translational Science Award Grant from National Center for Research Resources, a component of the NIH [UL1TR000448]
- NIH Roadmap for Medical Research
- NCI Cancer Center Support Grant [P30CA091842]
- Hope Center Alafi Neuroimaging Laboratory - NIH Shared Instrumentation Grant [S10RR027552]
- Intellectual and Developmental Disabilities Research Center at Washington University - Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH Grant [U54HD087011]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD087011] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [P30CA091842] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000448, UL1TR002345] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027552] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007317] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS087632, T32NS007205, K12NS001690] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG013730, RF1AG013730] Funding Source: NIH RePORTER
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CCCTC-binding factor (CTCF) is an 11 zinc finger DNA-binding domain protein that regulates gene expression by modifying 3D chromatin structure. Human mutations in CTCF cause intellectual disability and autistic features. Knocking out Ctcf in mouse embryonic neurons is lethal by neonatal age, but the effects of CTCF deficiency in postnatal neurons are less well studied. We knocked out Ctcf postnatally in glutamatergic forebrain neurons under the control of Camk2a-Cre. Ctcf(loxP/loxP); Camk2a-Cre(+) (Ctcf CKO) mice of both sexes were viable and exhibited profound deficits in spatial learning/memory, impaired motor coordination, and decreased sociability by 4 months of age. Ctcf CKO mice also had reduced dendritic spine density in the hippocampus and cerebral cortex. Microarray analysis of mRNA from Ctcf CKO mouse hippocampus identified increased transcription of inflammation-related genes linked to microglia. Separate microarray analysis of mRNA isolated specifically from Ctcf CKO mouse hippocampal neurons by ribosomal affinity purification identified upregulation of chemokine signaling genes, suggesting crosstalk between neurons and microglia in Ctcf CKO hippocampus. Finally, we found that microglia in Ctcf CKO mouse hippocampus had abnormal morphology by Sholl analysis and increased immunostaining for CD68, a marker of microglial activation. Our findings confirm that Ctcf KO in postnatal neurons causes a neurobehavioral phenotype in mice and provide novel evidence that CTCF depletion leads to overexpression of inflammation-related genes and microglial dysfunction.
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