Dopamine Neurons Change the Type of Excitability in Response to Stimuli

International audienceThe 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

Membrane currents and pacemaking in corticotrophs and hiPSC-derived dopaminergic neurons

Many neural networks are required to function at particular frequencies. These processes are often driven by rhythmic, intrinsically generated electrical activity that is produced by cells described as pacemaker neurons. Two disease-relevant in-vitro models were investigated that display poorly understood pacemaker activity; AtT20 anterior pituitary corticotrophs and human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons. Using electrophysiology and Ca2+ imaging, gaps in our understanding of pacemaking in these cell types were investigated. For AtT20s, it was revealed that hormone secretion in this cell type is uncoupled from its electrical activity. Novel roles were found for T-type voltage-gated calcium channels (VGCCs) in pacemaking and for L-type VGCCs in maintaining intracellular Ca2+ concentrations. hiPSC-derived DA neurons were found to produce apparently spontaneous electrical activity in culture that was dependent upon L-type VGCCs. This pacemaking was not found to be intrinsic, instead being driven by and developing in parallel with synaptic input in culture. These DA neurons immunostained for the L-type VGCC subtype CaV1.3, which is involved in the death of DA neurons in Parkinson's disease. Using a novel cell death assay these neurons were found to be selectively susceptible to the DA toxin 6-hydroxydopamine but displayed a resistance to glutamate-induced excitotoxicity. Data here provides valuable information on the similarities and differences between these in-vitro models and their in-vivo counterparts. This allowed for an in-depth assessment of their suitability as models for their respective diseases, hopefully leading to the targeted, efficient design of studies that use these cell types