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

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 .