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Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons.
- Source :
-
Cerebral cortex (New York, N.Y. : 1991) [Cereb Cortex] 2018 Nov 01; Vol. 28 (11), pp. 3868-3879. - Publication Year :
- 2018
-
Abstract
- Human mutations in CNTNAP2 are associated with an array of neuropsychiatric and neurological syndromes, including speech and language disorders, epilepsy, and autism spectrum disorder (ASD). We examined Cntnap2's expression and function in GABAergic cortical interneurons (CINs), where its RNA is present at highest levels in chandelier neurons, PV+ neurons and VIP+ neurons. In vivo functions were studied using both constitutive Cntnap2 null mice and a transplantation assay, the latter to assess cell autonomous phenotypes of medial ganglionic eminence (MGE)-derived CINs. We found that Cntnap2 constitutive null mutants had normal numbers of MGE-derived CINs, but had reduced PV+ CINs. Transplantation assays showed that Cntnap2 cell autonomously regulated the physiology of parvalbumin (PV)+, fast-spiking CINs; no phenotypes were observed in somatostatin+, regular spiking, CINs. We also tested the effects of 4 human CNTNAP2 ASD missense mutations in vivo, and found that they impaired PV+ CIN development. Together, these data reveal that reduced CNTNAP2 function impairs PV+ CINs, a cell type with important roles in regulating cortical circuits.
- Subjects :
- Alleles
Animals
Autism Spectrum Disorder
Cell Adhesion Molecules, Neuronal metabolism
Extracellular Matrix Proteins metabolism
Female
Gene Expression Regulation, Developmental
HEK293 Cells
Humans
Male
Membrane Proteins genetics
Mice, Inbred C57BL
Mice, Knockout
Mutation, Missense
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Parvalbumins metabolism
Reelin Protein
Serine Endopeptidases metabolism
Somatosensory Cortex physiology
Telencephalon growth & development
GABAergic Neurons physiology
Interneurons physiology
Membrane Proteins physiology
Nerve Tissue Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2199
- Volume :
- 28
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cerebral cortex (New York, N.Y. : 1991)
- Publication Type :
- Academic Journal
- Accession number :
- 29028946
- Full Text :
- https://doi.org/10.1093/cercor/bhx248