The Therapeutic Mode of Action of 4-Aminopyridine in Cerebellar Ataxia

• DOI: 10.1523/jneurosci.3582-09.2010
• Publication Date: 2010-05-26T17:34:07Z
• Authors: Karina Alviña; Kamran Khodakhah
• Keywords: Patch-Clamp Techniques; Behavior, Animal; Cerebellar Ataxia; Dose-Response Relationship, Drug; Action Potentials; Excitatory Postsynaptic Potentials; In Vitro Techniques; Electric Stimulation; Mice, Mutant Strains; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Chlorzoxazone; 0302 clinical medicine; Animals, Newborn; Chorea; Cerebellum; Exploratory Behavior; Potassium Channel Blockers; Animals; 4-Aminopyridine

Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K+channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the Kv1 family of K+channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K+channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia.