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

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.Rhythmic activity paces signal transfer within brain circuits. Brain rhythms are believed to depend heavily on the networks of inhibitory interneurons (1–4). In addition to synaptic inputs, interneuron excitability in the hippocampus is determined by tonic GABA_A conductance (5, 6), which could thus contribute to hippocampal rhythmogenesis. Indeed, GABA transaminase inhibitor vigabatrin increases the ambient GABA concentration, enhancing the power of the theta-rhythm in rats (7). In mice expressing GFP under the GAD67 promoter the reduced levels of ambient GABA correlate with a decreased power of kainate-induced oscillations in vitro (8). The latter decrease is reversed by a GABA uptake inhibitor, guvacine, which raises ambient GABA. GABA release by astrocytes also increases the gamma oscillation power in hippocampal area CA1 in vivo (9). Intriguingly, in hippocampal slices of animals lacking δ subunit-containing GABA_A receptors (which mediate tonic conductance in many local cell types including interneurons) the average frequency of cholinergically induced gamma oscillations is increased, whereas the oscillation power tends to drop (10). However, cellular mechanisms underlying such phenomena remain poorly understood.One possible explanation is the influence of tonic GABA_A conductance on the firing pattern of interneurons. Activation of GABA_A receptors inhibits most neurons, through either membrane hyperpolarization or shunting or both (11). In the adult brain, a depolarizing action of GABA has also been reported in various cell types, including hippocampal interneurons (3, 12–15). GABAergic depolarization can prompt spike generation, thus countering the shunting effects (14, 16). Therefore, experimental evidence indicates that the net effect of GABA_A receptor activation combines the excitatory action of depolarization and the inhibitory consequences of shunting, with the latter prevailing when the GABA_A receptor conductance is sufficiently strong. As a result, increasing the tonic GABA_A signaling can have a biphasic effect on individual hippocampal interneurons: excitatory at weak conductances and inhibitory at strong (14). Here we find that weak tonic GABA_A conductance favors a more regular firing pattern of interneurons, thus facilitating synchronization of the CA3 network. In contrast, strong GABA_A conductance makes the firing pattern more dependent on the stochastic excitatory synaptic input, thus reducing network synchrony.