A Modeling Study Suggests Complementary Roles for GABA_A and NMDA Receptors and the SK Channel in Regulating the Firing Pattern in Midbrain Dopamine Neurons

Midbrain dopaminergic (DA) neurons in vivo exhibit two major firing patterns: single-spike firing and burst firing. The firing pattern expressed is dependent on both the intrinsic properties of the neurons and their excitatory and inhibitory synaptic inputs. Experimental data suggest that the activation of N-methyl-D-aspartate (NMDA) and GABA_A receptors is a crucial contributor to the initiation and suppression of burst firing, respectively, and that blocking Ca²⁺-activated potassium SK channels can facilitate burst firing. A multi-compartmental model of a DA neuron with a branching structure was developed and calibrated based on in vitro experimental data to explore the effects of different levels of activation of NMDA and GABA_A receptors as well as the modulation of the SK current on the firing activity. The simulated tonic activation of GABA_A receptors was calibrated by taking into account the difference in the electrotonic properties in vivo versus in vitro. Although NMDA-evoked currents are required for burst generation in the model, currents evoked by GABA_A-receptor activation can also regulate the firing pattern. For example, the model predicts that increasing the level of NMDA receptor activation can produce excessive depolarization that prevents burst firing, but a concurrent increase in the activation of GABA_A receptors can restore burst firing. Another prediction of the model is that blocking the SK channel current in vivo will facilitate bursting, but not as robustly as blocking the GABA_A receptors.