Tonic GABA _A conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network

Abstract

The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABA A conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABA A depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABA A conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABA A conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABA A conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns.tonic conductance | extrasynaptic signaling | oscillations

Ectopic Expression of α6 and δ GABAAReceptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

“…A role for tonic inhibition in controlling such synchronous activity is supported by recent findings that tonic conductance can control interneuron firing patterns and synchronization in CA3 interneurons bidirectionally, with increased tonic conductance favoring a decrease in synchrony (Pavlov et al, 2014). Thus, the current findings raise the interesting possibility that increasing tonic inhibition in some groups of interneurons could not only limit their firing during strong stimulation but also contribute to the control of excessive synchrony within the network.…”

“…To study the circuit effects of ectopic expression of the ␣6 and ␦ subunits in SOM neurons, we selected an in vitro experimental paradigm in which the potassium channel blocker 4-AP, in the presence of glutamate receptor blockers, induces GABA A R-mediated bursting in dentate granule cells (Otis and Mody, 1992;Avoli et al, 1996). We hypothesized that an increase in tonic inhibition in the hilar SOM neurons would reduce their activity, leading to a reduction in synchronous firing among these hilar neurons and a decrease in the frequency of GABA A R-mediated bursting in dentate granule cells.…”

Age-related changes in tonic activation of presynaptic versus extrasynaptic γ-amniobutyric acid type B receptors in rat medial prefrontal cortex

“…Further, given that our results revealed a net age related increase in activation of extrasynaptic GABA A and GABA B receptors, there are a number of challenging but fascinating questions that remain about the relative mechanistic contribution of these two types of inhibitory systems. In that regard it is interesting to note that in other systems tonic activation of GABA A receptors is consistently implicated in control of neuronal offset or gain (Pavlov, et al, 2009, Semyanov, et al, 2004), and in generation of patterned activity and neuronal synchrony (Pavlov, et al, 2014, Traub, et al, 1996). By contrast, GABA B receptors expressed by cortical pyramidal cells have been implicated in modulation of NMDA mediated calcium influx (Chalifoux and Carter, 2010), and voltage gated calcium channels (Chalifoux and Carter, 2011), and even in theoretical generation and direct experimental termination of an upstate that is likely to support persistent firing (Craig, et al, 2013, Mann, et al, 2009, Sanders, et al, 2013).…”

Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses

“…In many of these studies GABA-mediated depolarization was excitatory, but there are also examples of GABA depolarization having an inhibitory effect due to either current shunting or Na + channel inactivation (Willis, 1999;Song et al, 2011;Witschi et al, 2011). Whether GABA-mediated depolarization has an excitatory or inhibitory effect may be due to the level of GABAergic input, with low levels of tonic GABA input having an excitatory effect and higher levels being associated with inhibition, at least in mammalian neurons (Song et al, 2011;Pavlov et al, 2014). It is not known if a similar relationship exists within leech neurons.…”

“…The potential of BIC to modulate excitability of the N and P cells was also examined because such changes in excitability can be indicative of tonic modulation by GABA (Semyanov et al, 2004;Pavlov et al, 2014). Activity elicited by 1-6-nA current pulse (500-ms duration) was measured in the N and P cells prior to and following bath-application of 100 lM BIC.…”