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Cited by 89Ion channel regulation and functionNeurogenesis and neuroplasticity mechanismsNeuroscience and Neuropharmacology Research

A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration

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Kamijo, Satoshi, Ishii, Yuichiro, Horigane, Shin-ichiro, Suzuki, Kanzo, Ohkura, Masamichi, Nakai, Junichi, Fujii, Hajime, Takemoto-Kimura, Sayaka +1 more·2018·The Journal of Neuroscience
DOI 10.1523/jneurosci.2357-17.2018PMC PMC8174135
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Abstract

Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca2+ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCC during brain development remain unclear. Calcium signaling has been shown to be essential for neurodevelopmental processes such as sculpting of neurites, functional wiring, and fine tuning of growing networks. To investigate this relationship, we performed submembraneous calcium imaging using a membrane-tethered genetically encoded calcium indicator (GECI) Lck-G-CaMP7. We successfully recorded spontaneous regenerative calcium transients (SRCaTs) in developing mouse excitatory cortical neurons prepared from both sexes before synapse formation. SRCaTs originated locally in immature neurites independently of somatic calcium rises and were significantly more elevated in the axons than in dendrites. SRCaTs were not blocked by tetrodoxin, a Na+ channel blocker, but were strongly inhibited by hyperpolarization, suggesting a voltage-dependent source. Pharmacological and genetic manipulations revealed the critical importance of the Cav1.2 (CACNA1C) pore-forming subunit of L-type VGCCs, which were indeed expressed in immature mouse brains. Consistently, knocking out Cav1.2 resulted in significant alterations of neurite outgrowth. Furthermore, expression of a gain-of-function Cav1.2 mutant found in Timothy syndrome, an autosomal dominant multisystem disorder exhibiting syndromic autism, resulted in impaired radial migration of layer 2/3 excitatory neurons, whereas postnatal abrogation of Cav1.2 enhancement could rescue cortical malformation. Together, these lines of evidence suggest a critical role for spontaneous opening of L-type VGCCs in neural development and corticogenesis and indicate that L-type VGCCs might constitute a perinatal therapeutic target for neuropsychiatric calciochannelopathies. SIGNIFICANCE STATEMENT Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca2+ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCCs during brain development remain unclear. We here combined the latest Ca2+ indicator technology, quantitative pharmacology, and in utero electroporation and found a hitherto unsuspected role for L-type VGCCs in determining the Ca2+ signaling landscape of mouse immature neurons. We found that malfunctional L-type VGCCs in immature neurons before birth might cause errors in neuritic growth and cortical migration. Interestingly, the retarded corticogenesis phenotype was rescued by postnatal correction of L-type VGCC signal aberration. These findings suggest that L-type VGCCs might constitute a perinatal therapeutic target for neurodevelopment-associated psychiatric disorders.

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Authors
Kamijo, S., Ishii, Y., Horigane, S.-I., Suzuki, K., Ohkura, M., Nakai, J., Fujii, H., Takemoto-Kimura, S., & Bito, H.
Affiliations
  • The University of Tokyo (JP)
  • Research Institute of Environmental Medicine, Nagoya University (JP)
  • Saitama University (JP)
  • International Research Center for Neurointelligence, The University of Tokyo (JP)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2018-05-17
Volume
38
Issue
24
Pages
5551-5566
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2357-17.2018
PMC
PMC8174135
OpenAlex
W2803489199
Cited by
89
References
58
Citations by year
2026: 8 · 2025: 5 · 2024: 12 · 2023: 7 · 2022: 17 · 2021: 17 · 2020: 16 · 2019: 7
FWCI
3.56
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Takeda Science Foundation
  • University of Texas Southwestern Medical Center
  • Japan Foundation for Applied Enzymology
  • Japan Agency for Medical Research and Development (CREST, 15H05723)
  • Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering
  • Hitachi Global Foundation
  • University of California, San Diego
  • Japan Society for the Promotion of Science (17H06312, 26282217, #16H06536, 15H02358, 26830043, 16K13105, 15H05723, 17K13270, CREST, 16H04670)
  • Japan Science and Technology Agency (CREST)
  • Core Research for Evolutional Science and Technology
  • Precursory Research for Embryonic Science and Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
L-type calcium channels, Cav1.2, CACNA1C, neurite outgrowth, radial neuronal migration, cortical development, Timothy syndrome, autism spectrum disorder, schizophrenia, cortical excitatory neurons, layer 2/3 neurons, malformations of cortical development, neuropsychiatric disorders, brain development
MeSH terms
Neuronal Outgrowth, Animals, Cell Movement, Cerebral Cortex, Mice, Inbred C57BL, Mice, Inbred ICR, Calcium Signaling, Calcium Channels, L-Type, Mice, Neurogenesis, Neural Stem Cells

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