Inferior olive hypertrophy and cerebellar learning are both needed to explain ocular oscillations in oculopalatal tremor

A new model of cerebellar learning explains how the cerebellum can generate arbitrary output waveforms to adjust output timing in the classical delay conditioning. This model can also reproduce the low frequency ocular oscillations seen in oculopalatal tremor (OPT). A novel circuit in the cerebellum uses both interneurons (INs) and Purkinje cells (PC) to control timing. Brain lesions that cause OPT give rise to hypertrophy of the inferior olive (IO) and an increase in conductance through gap junctions among IO neurons. When our model is changed in this way, the heavily coupled IO becomes an oscillator and generates synchronous spike trains at 1-2 Hz. These synchronized spikes do not produce the large amplitude, aperiodic waveforms of OPT. However, the synchronized IO signal goes to the cerebellar cortex (flocculus) directly, on climbing fibres, and indirectly, on mossy fibres from the vestibular nuclei. This creates a pathological association between the IO pulse trains on mossy and climbing fibres in PC. Variable pendular ocular oscillations emerged from the cerebellum model after learning this association. Since electrotonic coupling of IO cells depends on connexin proteins, drugs that block gap junctions, such as anti-malarial agents, might provide a novel therapy for OPT.