Journal article
Astrocytic abnormalities in brain-specific Cacna1c -deficient mice: Implications for BBB impairment in neuropsychiatric diseases associated with CACNA1C mutations
Channels (Austin, Tex.), Vol.19(1), 2523788
12/2025
DOI: 10.1080/19336950.2025.2523788
PMCID: PMC12218471
PMID: 40574410
Abstract
Intronic genetic variants within the CACNA1C gene, which encodes the pore-forming alpha 1c subunit of the Cav1.2 L-type calcium channel, are significant risk factors for a multitude of neuropsychiatric disorders. In most cases, these intronic SNPs have been associated with reduced CACNA1C expression. Here, we demonstrate that targeted genetic deletion of Cacna1c in mouse brain leads to increased astrocyte reactivity, increased expression of aquaporin 4 (AQP4) in astrocytes adjacent to the blood–brain barrier (BBB), and neuroinflammation, including changes in the levels of brain chemokines and inflammatory cytokines. Astrocytes are vital for maintaining BBB integrity, with AQP4 predominantly expressed in astrocytic endfeet where it regulates water balance in the brain. This function is critical to brain health, and deterioration of the BBB is a major feature of virtually all forms of neuropsychiatric disease. Our results highlight a previously unrecognized role for CACNA1C in astrocytes at the BBB, which could be a major factor in how intronic CACNA1C SNPs broadly increase the risk of multiple forms of major neuropsychiatric disease.
Details
- Title: Subtitle
- Astrocytic abnormalities in brain-specific Cacna1c -deficient mice: Implications for BBB impairment in neuropsychiatric diseases associated with CACNA1C mutations
- Creators
- Yeojung Koh - Case Western Reserve UniversityMaria Noterman-Soulinthavong - University of VermontAnusha Bangalore - Case Western Reserve UniversityUapingena P Kandjoze - Earlham CollegeZea Bud - Case Western Reserve UniversityKamryn L Noel - Case Western Reserve UniversityHami Lee - Temple UniversityKathryn Franke - Case Western Reserve UniversityCoral J Cintrón-Pérez - University Hospitals of ClevelandAnjali M Rajadhyaksha - Temple UniversityEric B Taylor - University of IowaAndrew A Pieper - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- Channels (Austin, Tex.), Vol.19(1), 2523788
- DOI
- 10.1080/19336950.2025.2523788
- PMID
- 40574410
- PMCID
- PMC12218471
- NLM abbreviation
- Channels (Austin)
- ISSN
- 1933-6969
- eISSN
- 1933-6969
- Publisher
- Taylor & Francis
- Grant note
- Valour FoundationWick FoundationMeisel & Pesses Family FoundationDepartment of Veterans Affairs Merit Award: I01BX005976 Morley-Mather Chair in Neuropsychiatry of University Hospitals of Cleveland Medical CenterAmerican Heart AssociationPaul Allen Foundation Initiative in Brain Health and Cognitive Impairment: 19PABH134580006 NIH/NIA: R01AG071512, R01AG066707, U01AG073323, F99AG083111 Louis Stokes VA Medical Center resources and facilitiesLincoln Neurotherapeutics Research FundLeonard Krieger Fund of the Cleveland FoundationNIH/NIDDK: R01 DK104998 University of Iowa Healthcare Distinguished Scholar AwardAmerican Heart Association Summer Undergraduate Research Program of University HospitalsCase Western Reserve UniversityNIH/NIDA: R01 DA053261, R01 DA054368, R01 DA050454 NIH/NIMH: R01 MH125006
A.A.P. was supported by The Valour Foundation [N/A], the Wick Foundation, the Meisel & Pesses Family Foundation, Department of Veterans Affairs Merit Award [I01BX005976], and as the Rebecca E. Barchas, M.D., D.L.F.A.P.A. University Professor in Translational Psychiatry of Case Western Reserve University and the Morley-Mather Chair in Neuropsychiatry of University Hospitals of Cleveland Medical Center. A.A.P. was also supported by the American Heart Association and Paul Allen Foundation Initiative in Brain Health and Cognitive Impairment [19PABH134580006] and by NIH/NIA [R01AG071512]. A. A.P. also acknowledges support from NIH/NIA [R01AG066707], NIH/NIA [U01AG073323], the Louis Stokes VA Medical Center resources and facilities, the Lincoln Neurotherapeutics Research Fund, the Leonard Krieger Fund of the Cleveland Foundation, and an anonymous donor. E.B.T was supported by NIH/NIDDK [R01 DK104998] and a University of Iowa Healthcare Distinguished Scholar Award. Y.K. was supported by NIH/NIA [F99AG083111]. A.B. was supported as the Rebecca E. Barchas, M.D., D.L.F.A.P.A. Undergraduate Research Fellow. U.P.K. was supported by the American Heart Association Summer Undergraduate Research Program of University Hospitals and Case Western Reserve University. A.M.R. was supported by NIH/NIDA [R01 DA053261], [R01 DA054368], and [R01 DA050454], and by NIH/NIMH [R01 MH125006], Anoymous Donor
- Language
- English
- Date published
- 12/2025
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984833636602771
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