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. 2019 Jan 9;9:1523. doi: 10.3389/fphar.2018.01523

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Copyright © 2019 Neumann, Rudolph, Knutson, Li, Cook, Hentschke, Antkowiak and Drexler.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Actions of the GABA_A receptor antagonist bicuculline and the GABA_A receptor agonist isoguvacine on neuronal activity of neocortical slice cultures. (A) Cumulative sum of action potentials during the first 1000 ms of the averaged up state in the absence (control, black) and presence of 20 μM bicuculline (blue, n = 32). (B) Peri-event time histogram (PETH) of averaged neuronal up states in the absence (black) and presence of bicuculline (blue). For the analysis of actions of GABAergic modulators on neuronal activity we collected all up states, averaged and divided these into time bins of 5 ms. Then, we calculated the instantaneous frequency of action potential firing for each 5-ms time bin and plotted them against the time. In the presence of 20 μM bicuculline, activity is almost constantly higher compared to control condition. Lower part of the figure: effect size. An effect size of one would indicate that the neuronal activity is one standard deviation apart. A significant difference between the two conditions can be assumed if the 95% confidence interval (CI) does not cross the zero line. Here, the effect of bicuculline is slightly building up and most prominent after 800 ms from the beginning of the up state, marked by gray shadowing. (C) Actions of 10 and 50 μM isoguvacine on the normalized firing rate and the normalized length of down states given as boxplot. Isoguvacine depressed the averaged action potential firing rate to 0.64 (median, iqr = 0.42, n = 40, p = 0.00012, Mann–Whitney U-test compared to control condition) at 10 μM and to 0.07 (median, iqr = 0.16, n = 25, p < 0.0001) at 50 μM. Meanwhile, the averaged length of neuronal down states was prolonged by 10 μM isoguvacine to 2.59 (median, iqr = 4.03, n = 40, p < 0.0001) and to 13.66 (median, iqr = 17.1, n = 25, p = 0.000012) at a concentration of 50 μM. (D) Analysis of the actions of 50 μM isoguvacine within neuronal up states given as PETH plus corresponding effect size. The PETH of control (black) and 50 μM isoguvacine (orange) are virtually superimposable while the corresponding effect size swings round the zero line, indicating that isoguvacine does not primarily affect neuronal up states. Taken together this illustrates that isoguvacine is depressing neuronal activity in neocortical cultures from mice by prolonging neuronal down states while activity within up states is almost unaffected.