TY - JOUR
T1 - Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV + Cortical Interneurons
AU - Vogt, Daniel
AU - Cho, Kathleen K.A.
AU - Shelton, Samantha M.
AU - Paul, Anirban
AU - Huang, Z. Josh
AU - Sohal, Vikaas S.
AU - Rubenstein, John L.R.
N1 - Funding Information:
This work was supported by: UCSF CTSI Pilot grant (# 1111111) to D.V.; NIMH (1K99MH108720) to K.K.A.C.; CIRM (# TB1-01190) to S.M.S.; BRAIN initiative U01 MH105948 to V.S.S.; Nina Ireland, NIMH R01 (# MH081880), NIMH R37 (# MH049428), and Simons Foundation (SFARI #309279) to J.L.R.R.
Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
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U2 - 10.1093/cercor/bhx248
DO - 10.1093/cercor/bhx248
M3 - Article
C2 - 29028946
AN - SCOPUS:85046895826
SN - 1047-3211
VL - 28
SP - 3868
EP - 3879
JO - Cerebral Cortex
JF - Cerebral Cortex
IS - 11
ER -