The importance of T currents in the control of
The importance of T-currents in the control of thalamic GABA synaptic function is also demonstrated by the presence of T-channel-dependent long-term synaptic plasticity, either potentiation (LTP) or depression (LTD). Indeed, in the associative posterior thalamic medial nucleus, an LTP of the GABAergic synapses is triggered by postsynaptic repetitive LTS-associated bursting activities in TC neurons (Sieber et al., 2013) (Fig. 4A). LTSs provided a depolarizing drive throughout the dendritic arbor (Connelly et al., 2015) that activated high-voltage L-type calcium currents. The subsequent rise in intracellular calcium induced the production of nitric oxide, retrogradely activating presynaptic guanylyl cyclase and increasing GABA release probability (Sieber et al., 2013). In contrast, at the inhibitory synapses between NRT and primary sensory TC neurons, Pigeat et al. described an LTD (Pigeat et al., 2015) (Fig. 4B) that is triggered by pairing the stimulation of the reticulothalamic input to rhythmic activation of post-synaptic T-currents, mimicking the pattern of LTSs occurrence during sleep delta waves. Importantly, this LTD mechanism required a specific funnelling of calcium though the T-channels and could not be triggered by Ca2+ entry through other members of the voltage-dependent Ca2+ channel family. The large influx of calcium through T-channels leads to the activation of the calcium-sensitive phosphatase calcineurin that dephosphorylates the GABAA receptors inducing their long-term desensitization. Therefore, the strict requirement of T-channel activation to trigger LTD of the GABAergic synapses suggests the existence of preferential links between these ret inhibitor and other partners of the synaptic plasticity, such as GABAA receptors and/or calcineurin. Such interactions including direct protein–protein interactions have already been described between T-channels and other ionic channels (Anderson et al., 2010, Anderson et al., 2013, Engbers et al., 2012), but data demonstrating colocalization of GABAA receptors or calcineurin with T-channels are still lacking. In contrast to the LTP described in the posterior thalamic medial nucleus (Sieber et al., 2013), the LTD in primary sensory nuclei did not affect all GABAergic synapses but only a subset of NRT synapses (Pigeat et al., 2015). Indeed, transient application of GABAA receptors antagonist during the induction protocol demonstrated that the LTD was only triggered at activated GABAA synapses. Finally, it should be noted that this LTD is both homosynaptic and heterosynaptic as it is also closely gated by glutamate released from the corticothalamic afferents that activates metabotropic receptors on the post-synaptic TC neurons. Therefore, the crucial relationship between the intrathalamic GABA drive and the T-channel activity, as a main actor of both sensory information transfer and oscillatory susceptibility of the thalamocortical network, is finely tuned by the cortical feedback itself (Pigeat et al., 2015). In conclusion, although different in term of signs and mechanisms, these two studies clearly highlight that GABAergic synaptic responses are dynamically modulated by T-channel activation. Overall, from the analysis of the results summarized so far, a clear picture emerges of a bidirectional relationship between GABA receptors and T-channels that shapes the excitability of the thalamocortical system (see Fig. 5).
Perspective This review mainly focuses on the inhibitory synapses between NRT afferents and TC neurons located in primary sensory nuclei. However, thalamic neurons localized in the other thalamic nuclei (higher order sensory nuclei, motor nuclei, midline and intralaminar nuclei) received, in addition to NRT afferents, inhibitory inputs originating from extra-thalamic sources, mainly basal ganglia, zona incerta, anterior pretectum and pontine reticular formation that can also evoked rebound LTS in TC neurons (Halassa and Acsady, 2016, Wanaverbecq et al., 2008). In contrast to the NRT GABAergic synapses, single axon terminals from the extra-thalamic GABAergic sources contact the postsynaptic TC neuron via several active zones wrapped in a glial cover that probably restrict GABA spillover. Moreover, while NRT to TC neuron synapses show a marked paired-pulse depression (Bessaih et al., 2006), these GABAergic synapses of extrathalamic origin display little short-term plasticity (Giber et al., 2015, Wanaverbecq et al., 2008) supporting a more faithful transmission. Whether the complex bidirectional relationships described here between activation of GABA receptors and T-currents also contribute to the regulation of the excitability of these non-NRT inhibitory synapses remains to be investigated.