Journal article
Enhancing GABAergic tonic inhibition reduces seizure-like activity in the neonatal mouse hippocampus and neocortex
The Journal of neuroscience, Vol.44(7), e1342232023
02/14/2024
DOI: 10.1523/JNEUROSCI.1342-23.2023
PMCID: PMC10869160
PMID: 38176909
Abstract
Around one-third of neonatal seizures do not respond to first-line anticonvulsants, including phenobarbital, which enhances phasic inhibition. Whether enhancing tonic inhibition decreases seizure-like activity in the neonate when GABA is mainly depolarizing at this age is unknown. We evaluated if increasing tonic inhibition using THIP (4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, Gaboxadol), a δ-subunit-selective GABA
receptor agonist, decreases seizure-like activity in neonatal C57BL/6J mice (postnatal day P5-8, both sexes) using acute brain slices. Whole-cell patch-clamp recordings showed that THIP enhanced GABAergic tonic inhibitory conductances in layer V neocortical and CA1 pyramidal neurons and increased their rheobase without altering sEPSCs characteristics. Two-photon calcium imaging demonstrated that enhancing the activity of extrasynaptic GABA
Rs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the Low-Mg
model of pharmacoresistant seizures, THIP reduced epileptiform activity in the neocortex and CA1 hippocampal region of neonatal and adult brain slices in a dose-dependent manner. We conclude that neocortical layer V and CA1 pyramidal neurons have tonic inhibitory conductances, and when enhanced, they reduce neuronal firing and decrease seizure-like activity. Therefore, augmenting tonic inhibition could be a viable approach for treating neonatal seizures.
Neonatal seizures occur in roughly 1-3/1000 term births and 10-fold more frequently in preterm neonates. Around 30-50% of neonatal seizures resist current treatments, and drug resistance often develops if diagnosis and treatment are delayed, for example, in underserved areas. There has been no significant improvement in treating neonatal seizures for nearly 50 years, especially for patients in whom pharmacoresistance develops. Our results show that enhancing tonic inhibition in neonatal mice, a developmental age when GABA mainly depolarizes, decreases neuronal firing and epileptiform activity
Our results suggest that augmenting tonic inhibition could be an alternative treatment for neonatal seizures, especially in pharmacy-resistant ones.
Details
- Title: Subtitle
- Enhancing GABAergic tonic inhibition reduces seizure-like activity in the neonatal mouse hippocampus and neocortex
- Creators
- G T Liddiard - Interdisciplinary Graduate Program in Neuroscience. The University of Iowa, Iowa City, Iowa 52242P S Suryavanshi - Stead Family Department of Pediatrics, Iowa Neuroscience Institute. The University of Iowa, Iowa City, Iowa 52242J Glykys - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.44(7), e1342232023
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.1342-23.2023
- PMID
- 38176909
- PMCID
- PMC10869160
- eISSN
- 1529-2401
- Grant note
- name: NIH/NINDS, award: R01NS115800; name: University of Iowa Hawkeye Intellectual and Developmental Disabilities Research Center, award: P50 HD10355; name: Iowa Neuroscience Institute
- Language
- English
- Electronic publication date
- 01/04/2024
- Date published
- 02/14/2024
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984539439002771
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