Dopaminergic local circuit neurons in the retina (DA cells) show robust, spontaneous, tetrodotoxin-sensitive pacemaking. To investigate the mechanism underlying this behavior, we characterized the sodium current and a subset of the potassium currents in the cells in voltage-clamp experiments. We found that there is a persistent component of the sodium current in DA cells which activates at more depolarized potentials than the transient component of the current. The transient component was completely inactivated at -50 mV, but DA cells remained able to fire spontaneous action potentials when potassium channels were partially blocked and the membrane potential remained above -40 mV. Based on these electrophysiological data, we developed a reduced computer model that reproduced the major features of DA cells. In simulations at the physiological resting potential, the persistent component of the sodium current was both necessary and sufficient to account for spontaneous activity, and the major contribution of the transient component of the sodium current was to initiate the depolarization of the model cell during the interspike interval. When tonic inhibition was simulated by lowering the input impedance of the model cell, the transient component played a larger role.
Isolated dopaminergic amacrine (DA) cells in mouse retina fire rhythmic, spontaneous action potentials and respond to depolarizing current with trains of low-frequency action potentials. To investigate the roles of voltage-gated ion channels in these processes, the transient A-type K+ current (I(K,A)) and Ca2+ current (I(Ca)) in isolated mouse DA cells were analyzed by voltage clamp. The I(K,A) activated at -60 mV and inactivated rapidly. I(Ca) activated at around -30 mV and reached a peak at 10 mV without apparent inactivation. We also extended our previous computational model of the mouse DA cell to include the new electrophysiological data. The model consisted of a membrane capacitance in parallel with eight currents: Na+ transient (I(Na,T)), Na+ persistent (I(Na,P)), delayed rectifier potassium (I(Kdr)), I(K,A), calcium-dependent potassium (I(K,Ca)), L-type Ca2+ I(Ca), hyperpolarization-activated cation current (I(h)), and a leak current (I(L)). Hodgkin-Huxley type equations were used to define the voltage- and time-dependent activation and inactivation. The simulations were implemented using the neurosimulator SNNAP. The model DA cell was spontaneously active from a wide range of initial membrane potentials. The spontaneous action potentials reached 35 mV at the peak and hyperpolarized to -76 mV between spikes. The spontaneous firing frequency in the model was 6 Hz. The model DA cell responded to prolonged depolarizing current injection by increasing its spiking frequency and eventually reaching a depolarization block at membrane potentials greater than -10 mV. The most important current for determining the firing rate was I(K,A). When the amplitude of I(K,A) was decreased, the firing rate increased. I(Ca) and I(K,Ca) also affected the width of action potentials but had only minor effects on the firing rate. Ih affected the firing rate slightly but did not change the waveform of the action potentials.
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