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Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex
G T Liddiard1,2, P S Suryavanshi1, J Glykys3,2,4
1Stead Family Department of Pediatrics, Iowa Neuroscience Institute, The University of Iowa, Iowa City 52242, Iowa.
Insights
Enhancing tonic inhibition with THIP (gaboxadol) reduces neonatal seizure-like activity by decreasing neuronal firing. This suggests augmenting tonic inhibition is a potential treatment for neonatal seizures.
Area of Science:
- Neuroscience
- Epilepsy Research
- Neonatal Neurology
Background:
- Neonatal seizures are often resistant to standard anticonvulsants like phenobarbital.
- The role of tonic inhibition in neonatal seizure activity is not well understood, especially when GABA is depolarizing.
Purpose of the Study:
- To investigate if enhancing tonic inhibition using THIP (gaboxadol) can decrease seizure-like activity in neonatal mice.
- To determine the effects of THIP on neuronal excitability and GABAergic conductances in the neonatal brain.
Main Methods:
- Utilized acute brain slices from neonatal C57BL/6J mice (postnatal day P5-8).
- Employed whole-cell patch-clamp recordings to measure GABAergic tonic inhibitory conductances and neuronal excitability.
- Used two-photon calcium imaging to assess neuronal firing.
- Induced pharmacoresistant seizures using 4-aminopyridine and low-Mg2+ models.
Main Results:
- THIP, a selective GABAAR agonist, enhanced tonic inhibitory conductances in neocortical and CA1 pyramidal neurons.
- Increased neuronal rheobase and decreased neuronal firing were observed with THIP administration.
- THIP dose-dependently reduced epileptiform activity in both neonatal and adult brain slices.
Conclusions:
- Neonatal neocortical and CA1 pyramidal neurons possess tonic inhibitory conductances.
- Enhancing these tonic conductances with THIP reduces neuronal firing and seizure-like activity.
- Augmenting tonic inhibition represents a promising therapeutic strategy for neonatal seizures.
Abstract:
Approximately 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 GABAA 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 sEPSC characteristics. Two-photon calcium imaging demonstrated that enhancing the activity of extrasynaptic GABAARs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the low-Mg2+ 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.
