Transsynaptic entrainment of cerebellar nuclear cells by alternating currents in a frequency dependent manner

Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that is being tested clinically for treatment of a variety of neural disorders. Animal studies investigating the underlying mechanisms of tACS are scarce, and nearly absent in the cerebellum. In the present study, we applied 10-400 Hz alternating currents (AC) to the cerebellar cortex in ketamine/xylazine anesthetized rats. The spiking activity of cerebellar nuclear (CN) cells was transsynaptically entrained to the frequency of AC stimulation in an intensity and frequency-dependent manner. Interestingly, there was a tuning curve for modulation where the frequencies in the midrange (100 and 150 Hz) were more effective, although the stimulation frequency for maximum modulation differed for each CN cell with slight dependence on the stimulation amplitude. CN spikes were entrained with latencies of a few milliseconds with respect to the AC stimulation cycle. These short latencies and that the transsynaptic modulation of the CN cells can occur at such high frequencies strongly suggests that PC simple spike synchrony at millisecond time scales is the underlying mechanism for CN cell entrainment. These results show that subthreshold AC stimulation can induce such PC spike synchrony without resorting to supra-threshold pulse stimulation for precise timing. Transsynaptic entrainment of deep CN cells via cortical stimulation could help keep stimulation currents within safety limits in tACS applications, allowing development of tACS as an alternative treatment to deep cerebellar stimulation. Our results also provide a possible explanation for human trials of cerebellar stimulation where the functional impacts of tACS were frequency dependent.