Harmaline Attenuates Voltage - Sensitive Ca2+ Currents in Neurons of the Inferior Olive

Abstract

Purpose. Harmaline is one member of a class of tremorgenic harmala alkaloids that have been implicated in neuroprotective effects and neurodegenerative disorders. It has been reported to interact with several neurotransmitter receptors as well as ion exchangers and voltage-sensitive channels. One site of harmaline action in the brain is the inferior olive (IO). Either local or systemic harmaline injection has been reported to increase spiking rate and coherence in the inferior olive and this activation is thought to produce tremor and ataxia through inferior olivary neuron activation of target neurons in the cerebellum, but the cellular mechanism is not yet known. Methods. Here, we have performed whole cell voltage-clamp and current clamp recordings from olivary neurons in brain slices derived from newborn rats. Results. We found that both transient low-voltage activated (LVA) and sustained high voltage-activated (HVA) Ca2+ currents are significantly attenuated by 0.125 – 0.25 mM harmaline applied to the bath and that this attenuation is partially reversible. In current clamp recordings, spike-afterhyperpolarization complexes were evoked by brief positive current injections. Harmaline produced a small attenuation of spike amplitude, but large spike broadening associated with attenuation of the fast and medium afterhyperpolarization. Conclusion. Our data suggest that one mode of olivary neuron activation by harmaline involves attenuation of both HVA and LVA Ca2+ conductances and consequent attenuation of Ca2+-sensitive K+ conductances resulting in spike broadening and attenuation of the afterhyperpolarization. Both of HVA and LVA attenuation also suggests a role to regulate intracelluar Ca2+, thereby to protect neurons from apoptosis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.