Journal article
Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors
JCI insight, Vol.10(21), e196152
11/10/2025
DOI: 10.1172/jci.insight.196152
PMCID: PMC12643521
PMID: 40956609
Abstract
About one-third of neonatal seizures do not respond to the first-line anticonvulsant phenobarbital, which activates phasic inhibition and whose effectiveness decreases over time. Whether enhancing tonic inhibition can treat refractory seizures or status epilepticus in neonates remains uncertain. We evaluated the effect of recurrent seizure-like events (SLE) on α5- and δ-GABAAR subunit expression and tonic inhibition in neonatal C57BL/6J mice (P6-P9, both sexes) using acute brain slices. We investigated the impact of THIP (gaboxadol) on neonatal behavioral seizures, neuronal apoptosis, and neurodegeneration in vivo. We found neonatal neocortical expression of α5- and δ-GABAA receptor (GABAAR) subunits. Blocking α5-GABAARs with L-655,708 did not affect acute neonatal SLE, whereas enhancing δ-GABAARs with THDOC, a neurosteroid, reduced them. The α5- and δ-GABAAR membrane expression increased after 8 hours of neonatal SLE, and correlated with increased δ-mediated conductance, but not α5-mediated one. Enhancing tonic inhibition was more effective in reducing recurrent neonatal SLE (8 hours) compared to early treatment. Increasing tonic inhibition reduced the duration, severity, and number of kainic acid-induced in vivo neonatal behavioral seizures without increasing neurodegeneration or apoptosis. We conclude that recurrent neonatal seizures increase tonic inhibition. Therefore, enhancing tonic inhibition may be a treatment strategy for prolonged neonatal status epilepticus.
Details
- Title: Subtitle
- Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors
- Creators
- Gage T Liddiard - University of IowaGordon F Buchanan - University of IowaMark L Schultz - University of IowaJoseph Glykys - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.10(21), e196152
- DOI
- 10.1172/jci.insight.196152
- PMID
- 40956609
- PMCID
- PMC12643521
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- NIH/National Institute of Neurological Disorders and Stroke: R01NS115800 Iowa Neuroscience InstituteUniversity of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center: P50 HD10355 University of Iowa Interdisciplinary Graduate Program in Neuroscience's training grant: NS007421 University of Iowa Medical Scientist Training Program's training grant: 5T32GM139776-04
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central.JG by NIH/National Institute of Neurological Disorders and Stroke R01NS115800 and the Iowa Neuroscience Institute.The University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center P50 HD10355.The University of Iowa Interdisciplinary Graduate Program in Neuroscience's training grant (NS007421) .The University of Iowa Medical Scientist Training Program's training grant (5T32GM139776-04) .
- Language
- English
- Electronic publication date
- 09/16/2025
- Date published
- 11/10/2025
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Neurology (Pediatrics)
- Record Identifier
- 9984964236102771
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