Objective: Understanding the drug effects with respect to various ion channels on subthalamic nucleus (STN) cells is the key to safety pharmacology assessment. Here our goal is to demonstrate the ability of computational models to simulate the effect of drugs for L-type and T-type calcium channels on the electrical activity of the STN cells, at the level of the bursting firing pattern.

Background: Deep brain stimulation (DBS) at the subthalamic nucleus (STN) has been a new and promising treatment of Parkinson’s disease (PD). STN neurons could discharge in the single-spike or the burst modes, but a significant increase in STN burst discharges has been documented in dopamine-deprived conditions such as PD.

Methods: The cell membrane is described as an equivalent electrical circuit consisting of a membrane capacitance connected in parallel with a number of variable conductance representing the ion channels. The ionic currents are described by differential equations, in terms of maximal conductance, electro chemical gradients, and voltage-dependent activation/inactivation gating variables. A drug model is introduced using an ion channel conductance block for the voltage gated Ca2+ (T – type and L- type) channels.

Results: The STN cell fires action potentials (AP) in the single spike mode with a resting membrane potential (RMP) of approximately -50 mV. The RMP is determined mostly by the balance between depolarizing currents through T – type Ca2+ channel and repolarizing currents through voltage gated and calcium activated potassium channels.The hyperpolarization of STN neurons promotes T-type Ca2+ channels from inactivation and a hyperpolarizing current injection generates burst mode of firing when the RMP is approximately -65 mV. The L-type Ca2+ channel with zero conductances abolished burst firings in STN model and relatively low conductance of T-type Ca2+abolishes the initial rising phase of the burst plateau and then shortens the burst duration.

Conclusions: The essential role of T-type and L-type Ca2+ currents in the genesis of burst discharges has been established in this silico STN model. These studies shed light in proper dosing of T-type and L-type calcium channel inhibitors as an effective new non-dopaminergic alternative in Parkinsonian patients, especially to overcome high-dose levodopa therapy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/computational-assessment-of-calcium-channel-effects-on-subthalamic-nucleus-neuronal-cells-study-of-abnormal-bursting-patterns-in-parkinsons-disease/