Nonlinear relationship between CAN current and Ca2+ influx underpins synergistic action of muscarinic and NMDA receptors on bursts induction in midbrain dopaminergic neurons

Bursting of midbrain dopamine (DA) neurons is believed to represent an important reward signal that instructs and reinforces goal-directed behaviors. In DA neurons, many afferents, including cholinergic and glutamatergic inputs, induce bursting, and it is suggested that a synergy exists between these afferents in bursting induction. However, the underlying mechanisms of the role and the synergy of muscarinic receptors (mAChRs) and NMDA receptors (NMDARs) in bursting induction remain unclear. Present work bestowed analysis using a mathematical model of DA neurons to demonstrate the underlying mechanisms. Activation of mAChRs, leading to rapid translocation of TRPC channels to cell surface, recruited Ca2+-activated nonspecific (CAN) current (I-CAN), meanwhile NMDARs excitation triggered Ca2+ influx, which induced the positive feedback loop of Ca2+ and I-CAN, respectively, yielded a robust ramping depolarization with a superimposed high-frequency spiking. In some DA cells, neither NMDARs nor mAChRs induced positive feedback loop unless they were activated simultaneously to induce bursting. Our experimental results verified those theoretical findings. These together unveil the underlying mechanisms of the role and synergy of mAChRs and NMDARs in bursting induction emerge from the nonlinear relationship between Ca2+ influx and I-CAN. Given the diverse and complex nature of neural circuitry and the DA neuron heterogeneity, our work provides new insights to understand specific afferents, the synergy between those afferents, and the differences in intrinsic excitability to be integrated by the bursting to accurately characterize the dopamine signals in the valances of reward and reinforcement, and a broad spectrum of neuropsychiatric disorders.

Automated summary

This study used a mathematical model to analyze the mechanisms and synergy between muscarinic receptors (mAChRs) and NMDA receptors (NMDARs) in bursting induction of dopamine (DA) neurons. The findings provide new insights into the specific afferents and their synergy, contributing to a better understanding of dopamine signals and neuropsychiatric disorders.