Abstract
The dynamics of neuronal excitability determine the neuron’s response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency “balanced” state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or co-activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization by mutual excitation.
Highlights
Midbrain dopamine (DA) neurons predominantly fire in a low frequency, metronomic manner and display occasional, yet functionally important, high frequency, burst-like episodes [1,2]
We investigated the excitability type of the DA neuron and found that, depending on the synaptic and intrinsic current composition, DA neurons can switch from type I to type II excitability
We investigated the behavior of a simulated dopamine neuron in response to irregular asynchronous GABA and glutamate (Glu) inputs to mimic temporal structure of neural firing in in vivo conditions
Summary
Midbrain dopamine (DA) neurons predominantly fire in a low frequency, metronomic manner (i.e. tonic) and display occasional, yet functionally important, high frequency, burst-like episodes [1,2]. A number of experimental [7,8,9,10,11,12,13,14,15,16,17,18,19] studies suggests that the maintenance of tonic firing in at least a subpopulation of DA neurons relies on the interactions of the voltage gated calcium (Ca2+) and SK-type Ca2+-dependent potassium (K+) currents Slow pacemaking in our model relies on a subthreshold Ca2+-K+ oscillatory mechanism, similar to a number of well-established models [4,20,21,22,23,24]. We use recent experiments to calibrate the dynamical properties of the DA neuron and determine its excitability type
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