Phasic, Nonsynaptic GABA-A Receptor-Mediated Inhibition Entrains Thalamocortical Oscillations

Abstract

GABA-A receptors (GABA-ARs) are typically expressed at synaptic or nonsynaptic sites mediating phasic and tonic inhibition, respectively. These two forms of inhibition conjointly control various network oscillations. To disentangle their roles in thalamocortical rhythms, we focally deleted synaptic, ␥2 subunit-containing GABA-ARs in the thalamus using viral intervention in mice. After successful removal of ␥2 subunit clusters, spontaneous and evoked GABAergic synaptic currents disappeared in thalamocortical cells when the presynaptic, reticular thalamic (nRT) neurons fired in tonic mode. However, when nRT cells fired in burst mode, slow phasic GABA-ARmediated events persisted, indicating a dynamic, burst-specific recruitment of nonsynaptic GABA-ARs. In vivo, removal of synaptic GABA-ARs reduced the firing of individual thalamocortical cells but did not abolish slow oscillations or sleep spindles. We conclude that nonsynaptic GABA-ARs are recruited in a phasic manner specifically during burst firing of nRT cells and provide sufficient GABA-AR activation to control major thalamocortical oscillations.

Thalamic Inhibition: Diverse Sources, Diverse Scales

“…For the TRN, this would mean enhanced bursting during these states resulting in more widespread and longer-lasting inhibition of thalamic targets. The effect of TRN bursting is hugely aggravated by a firing pattern dependent transmitter release mechanism [46]. During tonic spikes GABA predominantly activates synaptic GABA-A receptors, however during bursts GABA spills over to extrasynaptic receptors as well resulting in large, several hundred msec long burst IPSCs [46,47] (Fig 2C–E) switching the temporal scale of inhibitory action.…”

“…The effect of TRN bursting is hugely aggravated by a firing pattern dependent transmitter release mechanism [46]. During tonic spikes GABA predominantly activates synaptic GABA-A receptors, however during bursts GABA spills over to extrasynaptic receptors as well resulting in large, several hundred msec long burst IPSCs [46,47] (Fig 2C–E) switching the temporal scale of inhibitory action. This spill-over is permitted by the lack of complete glia sheet around TRN terminals [15].…”

“…Instead, a strong possibility is that changes in their intrinsic properties and/or cortical inputs explain their disengagement. Progressive decrease in TRN bursting will result in a corresponding drop of TC inhibitory charge likely via the diminished extrasynaptic receptor activation [46] as indicated above. This will diminish TC rebound bursting and eventually terminate a spindle event.…”

“…In fact, paired recordings show that some TRN neurons are capable of exerting strong and reliable inhibition of their thalamic targets [75–77] especially in case of TRN bursts [46] (see above). Moreover, it has been shown that the axon of a single TRN neuron also establishes multisynaptic contacts with the TC cells.…”

“…This indicates that the duration of spindles is determined at the onset by the state of the network and this state is coded best by the activity level of TRN cells. Figures B,F,G from [51], C–E from [46]…”