Phasic GABA_A‐receptor activation is required to suppress epileptiform activity in the CA3 region of the immature rat hippocampus

Abstract

SUMMARYPurpose: Despite the consistent observation that c-aminobutyric acid A (GABA A ) receptors mediate excitatory responses at perinatal stages, the role of the GABAergic system in the generation of neonatal epileptiform activity remains controversial. Therefore, we analyzed whether tonic and phasic GABAergic transmission had differential effects on neuronal excitability during early development. Methods: We performed whole cell patch-clamp and field potential recordings in the CA3 region of hippocampal slices from immature (postnatal day 4-7) rats to analyze the effect of specific antagonists and modulators of tonic and phasic GABAergic components on neuronal excitability. Key Findings: The GABAergic antagonists gabazine (3 lM) and picrotoxin (100 lM) induced epileptiform discharges, whereas activation of GABA A receptors attenuated epileptiform discharges. Under low-Mg 2+ conditions, 100 nM gabazine and 1 lM picrotoxin were sufficient to provoke epileptiform activity in 63.2% (n = 19) and 53.8% (n = 26) of the slices, respectively. Whole-cell patchclamp experiments revealed that these concentrations significantly reduced the amplitude of phasic GABAergic postsynaptic currents but had no effect on tonic currents. In contrast, 1-lM 4,5,6,7-tetrahydroisoxaz-olo[5,4-c]-pyridin-3-ol (THIP) induced a tonic current of )12 ± 2.5 pA (n = 6) and provoked epileptiform discharges in 57% (n = 21) of the slices. Significance: We conclude from these results that in the early postnatal rat hippocampus a constant phasic synaptic activity is required to control excitability and prevent epileptiform activity, whereas tonic GABAergic currents can mediate excitatory responses. Pharmacologic intervention at comparable human developmental stages should consider these ambivalent GABAergic actions.

Taurine activates GABAergic networks in the neocortex of immature mice

“…However, in only 3 of these 15 cells bath-application of taurine reduced AP frequency. In order to unravel, whether the taurine-induced increase in AP frequency was caused by GABAergic PSCs or the depolarizing inward current, we next applied 300 μM taurine in the presence of low gabazine concentrations, which selectively inhibit phasic GABAergic currents (Stell and Mody, 2002; Kolbaev et al, 2012). Accordingly we were able to show that bath application of 0.3 μM gabazine completely blocked the taurine-induced increase in the frequency of GABAergic PSCs ( n = 7), while the tonic current was not significantly affected (94.9 ± 16.3%, n = 7).…”

Abnormal γ‐aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy

“…4). 37 Increased M-channel function of GABAergic interneurons in that area would result in disinhibition of principal neurons, and, consequently, hyperexcitability. (C) The duration of ictallike activity was reduced by 20 lM bicuculline methiodide (BMI; *p < 0.05, paired t-test), and recovered by wash out.…”

Role of tonic GABAergic currents during pre- and early postnatal rodent development

“…In the immature hippocampus a moderate increase in tonic GABAergic currents mediated by α5 containing receptors promote epileptiform discharges under low-Mg 2+ condition, which are insufficient to induce epileptiform discharges in this preparation (Kolbaev et al, 2012; Figure 4 ). In the hippocampus of early postnatal rats a tonic activation of GABA B receptors does not control basal or stimulated GABA release (Caillard et al, 1998), although the GABA B specific agonist Baclofen reduces the amplitude of GABAergic postsynaptic currents, indicating the functional expression of GABA B receptors in this structure (Caillard et al, 1998).…”

“…This proconvulsive THIP effect was prevented in the presence of the α5 selective antagonist L-655,708. Modified from Kolbaev et al (2012).…”