Modelling the spatial and temporal constrains of the GABAergic influence on neuronal excitability

Abstract GABA (γ-amino butyric acid) is an inhibitory neurotransmitter in the adult brain that can mediate depolarizing responses during development or after neuropathological insults. Under which conditions GABAergic membrane depolarizations are sufficient to impose excitatory effects is hard to predict, as shunting inhibition and GABAergic effects on spatiotemporal filtering of excitatory inputs must be considered. To evaluate at which reversal potential a net excitatory effect was imposed by GABA (E GABA Thr ), we performed a detailed in-silico study using simple neuronal topologies and distinct spatiotemporal relations between GABAergic and glutamatergic inputs. These simulations revealed for GABAergic synapses located at the soma an E GABA Thr close to action potential threshold (E AP Thr ), while with increasing dendritic distance E GABA Thr shifted to positive values. The impact of GABA on AMPA-mediated inputs revealed a complex temporal and spatial dependency. E GABA Thr depends on the temporal relation between GABA and AMPA inputs, with a striking negative shift in E GABA Thr for AMPA inputs appearing after the GABA input. The spatial dependency between GABA and AMPA inputs revealed a complex profile, with E GABA Thr being shifted to values negative to E AP Thr for AMPA synapses located proximally to the GABA input, while for distally located AMPA synapses the dendritic distance had only a minor effect on E GABA Thr . For tonic GABAergic conductances E GABA Thr was negative to E AP Thr over a wide range of g GABA tonic values. In summary, these results demonstrate that for several physiologically relevant situations E GABA Thr is negative to E AP Thr , suggesting that depolarizing GABAergic responses can mediate excitatory effects even if E GABA did not reach E AP Thr . Author summary The neurotransmitter GABA mediates an inhibitory action in the mature brain, while it was found that GABA provokes depolarizations in the immature brain of after neurological insults. It is, however, not clear to which extend these GABAergic depolarizations con contribute to an excitatory effect. In the present manuscript we approached this question with a computational model of a simplified neurons to determine which amount of a GABAergic depolarizing effect, which we quantified by the so called GABA reversal potential (E GABA ), was required to turn GABAergic inhibition to excitation. The results of our simulations revealed that if GABA was applied alone a GABAergic excitation was induced when E GABA was around the action potential threshold. When GABA was applied together with additional excitatory inputs, which is the physiological situation in the brain, only for spatially and temporally correlated inputs E GABA was close to the action potential threshold. For situations in which the additional excitatory inputs appear after the GABA input or are distant to the GABA input, an excitatory effect of GABA could be observed already at E GABA substantially negative to the action potential threshold. This results indicate that even slightly depolarizing GABA responses, which may be induced during or after neurological insults, can potentially turn GABAergic inhibition into GABAergic excitation.