Synergy of AMPA and NMDA receptor currents in dopaminergic neurons: a modeling study

Abstract

Dopaminergic (DA) neurons display two modes of firing: low-frequency tonic and high-frequency bursts. The high frequency firing within the bursts is attributed to NMDA, but not AMPA receptor activation. In our models of the DA neuron, both biophysical and abstract, the NMDA receptor current can significantly increase their firing frequency, whereas the AMPA receptor current is not able to evoke high-frequency activity and usually suppresses firing. However, both currents are produced by glutamate receptors and, consequently, are often co-activated. Here we consider combined influence of AMPA and NMDA synaptic input in the models of the DA neuron. Different types of neuronal activity (resting state, low frequency, or high frequency firing) are observed depending on the conductance of the AMPAR and NMDAR currents. In two models, biophysical and reduced, we show that the firing frequency increases more effectively if both receptors are co-activated for certain parameter values. In particular, in the more quantitative biophysical model, the maximal frequency is 40% greater than that with NMDAR alone. The dynamical mechanism of such frequency growth is explained in the framework of phase space evolution using the reduced model. In short, both the AMPAR and NMDAR currents flatten the voltage nullcline, providing the frequency increase, whereas only NMDA prevents complete unfolding of the nullcline, providing robust firing. Thus, we confirm a major role of the NMDAR in generating high-frequency firing and conclude that AMPAR activation further significantly increases the frequency.

Dopamine neurons change the type of excitability in response to stimuli

“…This is consistent with the previous modeling studies showing that NMDA can elicit bursting [56][57][58] or burst envelope [59], while AMPA abolishes high frequency firing. The dynamical explanation is that AMPAR activation shifts the minimum of the voltage nullcline across the Ca 2+ nullcline, so that for high AMPAR conductance values (as well as positive applied currents), voltage oscillations decrease in amplitude and depolarization block occurs ( S3B Fig). Thus, DA neuron firing does not exceed the frequency of~10 Hz when driven with AMPAR activation, similarly to the experimental results (see e.g.…”