| First Author | Liddiard GT | Year | 2024 |
| Journal | J Neurosci | Volume | 44 |
| Issue | 7 | PubMed ID | 38176909 |
| Mgi Jnum | J:354277 | Mgi Id | MGI:7730949 |
| Doi | 10.1523/JNEUROSCI.1342-23.2023 | Citation | Liddiard GT, et al. (2024) Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex. J Neurosci 44(7) |
| abstractText | 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 delta-subunit-selective GABA(A) 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 GABA(A)Rs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the low-Mg(2+) 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. |
