Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

Abstract

T-type Ca2+ channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through Ttype channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for Ca V 3.1, the gene for T-type Ca 2+ channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit. S leep spindles are one type of several rhythmic brain waves detected by electroencephalography (EEG) during normal non-rapid eye movement (NREM) sleep. A spindle consists of characteristic waxing-and-waning field potentials grouped into 7-to 14-Hz oscillations that last for 1-3 s and recur once every 5-10 s in the thalamus and the cortex (1-3). Spindles are also visible under anesthesia, particularly with barbiturates but also with ketamine-xylazine combinations (4, 5). These oscillations are generated in the thalamus as a result of synaptic interactions between inhibitory [i.e., thalamic reticular nucleus (TRN)] neurons and excitatory thalamocortical (TC) neurons, and are propagated to the cortex. Corticothalamic projections back to the thalamus complete the cortico-thalamo-cortical loop.In vivo data suggest that TRN neurons are spindle pacemakers, because spindles can be generated in deafferented TRN neurons (6) but disappear in TC regions after disconnection from TRN neurons (7). However, in vitro data suggest that an intact TC-TRN network is a necessity, because spindles are abolished after disconnection of TC and TRN neurons (8).Two distinct firing patterns, tonic and burst, are displayed by both TRN and TC neurons. Burst firing is mediated by lowthreshold T-type Ca 2+ channels (9). Of the three subtypes of T-type channels, Ca V 3.1 is expre...

Cortical control of adaptation and sensory relay mode in the thalamus

“…These controls further support the finding that L6 activity leads to a smaller LTS and fewer burst APs by inducing a more positive RPM. In summary, L6 input to VPM neurons decreases burstiness by inactivating T-type Ca 2+ channels via depolarization, in line with the dependence of burst firing on T-type Ca 2+ channels and the biophysical properties of thalamic relay neurons (17,28,31).…”

Timing matters: open‐loop stimulation does not improve overnight consolidation of word pairs in humans

“…This has also been found with electric stimulation in the lateroposterior thalamic nucleus of anesthetized cats, where a locally induced spindle, out of phase with the endogenous rhythm, prevented the occurrence of the next endogenous spindle in the same location (Contreras et al ., ). In order to generate spindles, neurons in the reticular nucleus have to be sufficiently hyperpolarized, so that low‐threshold Ca 2+ currents can deinactivate and initiate bursting (Astori et al ., ; Lee et al ., ). On the other hand, a much increased level of hyperpolarization prevents spindle oscillations and instead gives rise to thalamic delta oscillations (Nunez et al ., ).…”

Brain state dependent activity in the cortex and thalamus

“…In the slow-wave sleep state, these thalamocortical neurons are hyperpolarized, in part owing to the withdrawal of neuromodulatory transmitters[29]. The depolarizing ending phase of IPSP can initiate a low threshold Ca 2+ spike when thalamocortical neurons are in this state, and thus initiate a burst of action potentials (although it is not clear if these Ca 2+ spike-mediated bursts are absolutely essential for the generation of spindles; [32]). Since thalamocortical neurons excite nRt neurons, these GABAergic cells are once again activated, resulting in the initiation of the next cycle of the spindle wave.…”