Coupled oscillator model of the dopaminergic neuron of the substantia nigra

Calcium imaging using fura-2 and whole cell recording revealed the effectiv e location of the oscillator mechanism on dopaminergic neurons of the subst antia nigra, pars compacta; in slices from rats aged 15-20 days. As previou sly reported, dopaminergic neurons fired in a slow rhythmic single spiking pattern. The underlying membrane potential oscillation survived blockade of sodium currents with TTX and was enhanced by blockade of voltage-sensitive potassium currents with TEA. Calcium levels increased during the subthresh old depolarizing phase of the membrane potential oscillation and peaked at the onset of the hyperpolarizing phase as expected if the pacemaker potenti al were due to a low-threshold calcium current and the hyperpolarizing phas e to calcium-dependent potassium current. Calcium oscillations were synchro nous in the dendrites and soma and were greater in the dendrites than in th e soma. Average calcium levels in the dendrites overshot steady-state level s and decayed over the course of seconds after the oscillation was resumed after having been halted by hyperpolarizing currents. Average calcium level s in the soma increased slowly, taking many cycles to achieve steady state. Voltage clamp with calcium imaging revealed the voltage dependence of the somatic calcium current without the artifacts of incomplete spatial voltage control. This showed that the calcium current had little or no inactivatio n and was half-maximal at -40 to -30 mV. The time constant of calcium remov al was measured by the return of calcium to resting levels and depended on diameter. The calcium sensitivity of the calcium-dependent potassium curren t was estimated by plotting the slow tail current against calcium concentra tion during the decay of calcium to resting levels at -60 mV. A single comp artment model of the dopaminergic neuron consisting of a noninactivating lo w-threshold calcium current, a calcium-dependent potassium current, and a s mall leak current reproduced most features of the membrane potential oscill ations. The same currents much more accurately reproduced the calcium trans ients when distributed uniformly along a tapering cable in a multicompartme nt model. This model represented the dopaminergic neuron as a set of electr ically coupled oscillators with different natural frequencies. Each frequen cy was determined by the surface area to volume ratio of the compartment. T his model could account for additional features of the dopaminergic neurons seen in slices, such as slow adaptation of oscillation frequency and may p roduce irregular firing under different coupling conditions.