Mutations of CNTNAP1 led to defects in neuronal development
Wanxing Li, … , Zilong Qiu, Wenhao Zhou
Wanxing Li, … , Zilong Qiu, Wenhao Zhou
Published November 5, 2020
Citation Information: JCI Insight. 2020;5(21):e135697. https://doi.org/10.1172/jci.insight.135697.
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Research Article Genetics Neuroscience

Mutations of CNTNAP1 led to defects in neuronal development

Abstract

Mutations of CNTNAP1 were associated with myelination disorders, suggesting the role of CNTNAP1 in myelination processes. Whether CNTNAP1 may have a role in early cortical neuronal development is largely unknown. In this study, we identified 4 compound heterozygous mutations of CNTNAP1 in 2 Chinese families. Using mouse models, we found that CNTNAP1 is highly expressed in neurons and is located predominantly in MAP2+ neurons during the early developmental stage. Importantly, Cntnap1 deficiency results in aberrant dendritic growth and spine development in vitro and in vivo, and it delayed migration of cortical neurons during early development. Finally, we found that the number of parvalbumin+ neurons in the cortex and hippocampus of Cntnap1–/– mice is strikingly increased by P15, suggesting that excitation/inhibition balance is impaired. Together, this evidence elucidates a critical function of CNTNAP1 in cortical development, providing insights underlying molecular and circuit mechanisms of CNTNAP1-related disease.

Authors

Wanxing Li, Lin Yang, Chuanqing Tang, Kaiyi Liu, Yulan Lu, Huijun Wang, Kai Yan, Zilong Qiu, Wenhao Zhou

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Figure 7

Cntnap1–/– mice showed increased spine density and an increase in the number of PV+ and VIP+ neurons.

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Cntnap1–/– mice showed increased spine density and an increase in the n...
(A) Representative Golgi staining of cortical layers II/III of adult Cntnap1−/− mice (apical dendrites, 5 months of age, n = 3 for WT and Cntnap1−/− mice). Scale bar: 4 μm. (B) Costaining of Cntnap1 and PV in WT mouse brain at P15. Scale bar: 200 μm. (C) Representative immunochemical images of the S1 primary somatosensory cortex and hippocampus in coronal slices of P15 mouse brains stained with a PV antibody. Scale bar: 500 μm. (D) Quantitative analysis of spine density in Cntnap1–/– mice (22 and 25 neurons from each group were randomly selected and measured). Statistical significance was evaluated by Student’s t test. **P = 0.0093. Data are shown as mean ± SEM. (E and F) Quantitative analysis of the number of PV+ neurons in Cntnap1–/– mice (n = 3 mice for WT and KO) compared with their normal littermates. Statistical significance was evaluated by Student’s t test. Data are shown as mean ± SEM. For the quantification of PV+ neurons in cortex, ***P = 0.001. For the quantification of PV+ neurons in hippocampus, **P = 0.0025. (G and H) Representative immunochemical images of the S1 primary somatosensory cortex and hippocampus in coronal slices of P15 mouse brains stained with a VIP (green) and SST (red) antibody. Scale bar: 500 μm. On the right are enlarged images of boxed hippocampus stained with VIP antibody. (I and J) Quantitative analysis of the number of VIP+ and SST+ neurons in Cntnap1–/– mice compared with WT (n = 3 mice for WT and KO). For the quantification of VIP+ neurons in hippocampus, ***P = 0.0002. Statistical significance was evaluated by Student’s t test. Data are shown as mean ± SEM.