Nonlinear relationship between CAN current and $Ca^{2+}$ influx underpins synergistic action of muscarinic and NMDA receptors on bursts induction in midbrain dopaminergic neurons

Abstract

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 $Ca^{2+}$-activated nonspecific (CAN) current ($I_{CAN}$), meanwhile NMDARs excitation triggered $Ca^{2+}$ influx, which induced the positive feedback loop of $Ca^{2+}$ 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 $Ca^{2+}$ 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.