Bidirectional Modulation of Neuronal Responses by Depolarizing GABAergic Inputs

Abstract

The reversal potential of GABAA receptor channels is known to be less negative than the resting membrane potential under some cases. Recent electrophysiological experiments revealed that a GABAergic unitary conductance with such a depolarized reversal potential could not only prevent but also facilitate action potential generation depending on the timing of its application relative to the excitatory unitary conductance. Using a two-dimensional point neuron model, we simulate the experiments regarding the integration of unitary conductances, and execute bifurcation analysis. Then we extend our analysis to the case in which the neuron receives two kinds of periodic input trains-an excitatory one and a GABAergic one. We show that the periodic depolarizing GABAergic input train can modulate the output time-averaged firing rate bidirectionally, namely as an increase or a decrease, in a devil's-staircase-like manner depending on the phase difference with the excitatory input train. Bifurcation analysis reveals the existence of a wide variety of phase-locked solutions underlying such a graded response of the neuron. We examine how the input time-width and the value of the GABAA reversal potential affect the response. Moreover, considering a neuronal population, we show that depolarizing GABAergic inputs bidirectionally modulate the amplitude of the oscillatory population activity.

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

“…Combining measurements at the single-cell and network level, our data thereby show that, in vivo, depolarizing GABAergic transmission has additional inhibitory functions at the network level, likely via the GABA A R-dependent increase in membrane conductance (that is, shunting inhibition). This is in line with both conclusions derived from mathematical modelling and experimental in vitro data 22,23 . It has been hypothesized that, in the neonatal rodent visual cortex, the sequential activation of corresponding retinal and cortical domains is crucial for the proper establishment of retinotopic maps, as previously shown for the optic tectum 66 .…”

“…Our data further revealed that the generation of Ca 2 þ clusters in the occipital cortex is essentially independent of NKCC1-in spite of its cellular effects (see above). Computational modelling and experimental studies in vitro have extensively characterized the conditions under which a subthreshold-depolarizing GABAergic conductance may facilitate action potential discharge (excitatory sensu lato) or, alternatively, inhibit neuronal output [20][21][22][23][24] . Although not excluding excitatory sensu lato actions of GABA, our data are compatible with the view that these, if present, are not required to drive spontaneous cortical network activity.…”

“…Owing to an increase in membrane conductance, depolarizing GABAergic inputs may modulate neuronal output in a complex and bidirectional manner. Whether excitatory or inhibitory effects on neuronal firing dominate eventually depends on multiple parameters (including membrane potential, reversal potential of GABA A Rmediated currents, action potential threshold 20 , timing and location of inputs [21][22][23] as well as previous neuronal activity 24,25 ).…”

Activity‐dependent intracellular chloride accumulation and diffusion controls GABAA receptor‐mediated synaptic transmission

“…The complex role of depolarizing E GABA in network synchronization and excitability has recently been investigated in a num-ber of studies. The value of E GABA has been found to dramatically affect action potential generation and firing rate modulation (Gulledge and Stuart, 2003;Morita et al, 2006;Prescott et al, 2006;Saraga et al, 2008). Most importantly, E GABA interacts with such factors as the speed of the synapse, the synaptic delay, and the dynamics of spike generation to determine the stability and synchrony of neuronal oscillations (Jeong and Gutkin, 2005;Stiefel et al, 2005;Morita et al, 2006;Vida et al, 2006; see also Jedlicka and Backus, 2006).…”

Anion transport and GABA signaling

“…However, more recent results suggest that GABA A receptor activation also supports the generation of early neocortical network activity (Allene et al, 2008). It is worth noting that depolarizing GABA A -receptor activation not necessarily needs to be excitatory (Morita et al, 2005,2006). The GABA-induced increase in membrane conductance can also cause a so-called shunting inhibition, because according to Ohm's law, the drop in membrane resistance would decrease the voltage change caused by a certain depolarizing current (e.g., a glutamatergic synaptic input).…”