The role of regularity and synchrony of cerebellar Purkinje cells for pathological nystagmus

Previous theories assumed that the beneficial effect of the potassium channel blocker 4-aminopyridine (4-AP) for patients suffering from downbeat nystagmus (DBN) or episodic ataxia type 2 (EA2) is due to an increase of excitability of cerebellar Purkinje cells (PC). Recent experimental results using therapeutic doses of 4-AP with a mouse model of EA2 challenged the theory showing that 4-AP does not change the firing rate of PC but their regularity. Based on a mathematical model of the ocular motor and cerebellar circuitry, we show that changes in regularity have no effect without synchrony in PC firing. Together with synchronous firing, an increase in regularity may lead to a decrease in overall inhibition and may invert the inhibitory to an excitatory response due to imprinting, a novel effect of synchronized neural inhibition. Both effects are unlikely to be the causative mechanism for the success of 4-AP in treating cerebellar disorders.