Pharmacologic antagonism of CB1 receptors improves electrophysiological alterations in the 3-AP model of cerebellar ataxia

Abstract

Abstract Although ataxia is associated with cerebellar dysfunction, little is known about the effects of ataxia on Purkinje cell electrophysiological properties. Here, we evaluated these parameters in cerebellar vermis brain slices. Purkinje cells were exposed to aCSF (control) or to 1 mM 3-acetyl pyridine (3-AP) in the recording chamber. Effects of a cannabinoid agonist (WIN; 7.5 nmol), and a cannabinoid antagonist (AM; 20 nmol) were evaluated under both conditions. Exposure to 3-AP induced dramatic changes in cellular excitability that likely would affect Purkinje cell output. In whole-cell current clamp recordings, 3-AP exposed Purkinje cells demonstrated a significantly higher frequency of action potentials, a larger afterhyperpolarization (AHP), and a larger rebound of action potentials. In addition, 3-AP caused a significant decrease in the interspike interval (ISI), half-width, and decreased the first spike latency. Remarkably, the action potential frequency, AHP amplitude, rebound, ISI, action potential halfwidth, and first spike latency were no longer different from controls in 3-AP cells treated with AM. Sag percentage, on the other hand, showed no significant difference under any treatment condition indicating that cannabinoids' actions on ataxia-mediated Purkinje cell changes may not include effects on neuronal excitability through changes of Ih. These data show that cannabinoid antagonists reduce the excitability of Purkinje cells in an ex vivo model of ataxia and suggest their potential as therapeutics in cerebellar dysfunctions.