Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, EGABA: monotonically decreasing for sufficiently low EGABA (inhibitory), monotonically increasing for EGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of EGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of EGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.