Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Abstract

Despite the importance of somatodendritic dopamine (DA) release in the Substantia Nigra pars compacta (SNc), its mechanism remains poorly understood. Using a novel approach combining fast-scan controlled-adsorption voltammetry (FSCAV) and single-unit electrophysiology, we have investigated the mechanism of somatodendritic release by directly correlating basal (non-stimulated) extracellular DA concentration ([DA] ), with pharmacologically-induced changes of firing of nigral dopaminergic neurons in rat brain slices. FSCAV measurements indicated that basal [DA] in the SNc was 40.7 ± 2.0 nM (at 34 ± 0.5°C), which was enhanced by amphetamine, cocaine, and L-DOPA, and reduced by VMAT2 inhibitor, Ro4-1284. Complete inhibition of firing by TTX decreased basal [DA] , but this reduction was smaller than the effect of D receptor agonist, quinpirole. Despite similar effects on neuronal firing, the larger decrease in [DA] evoked by quinpirole was attributed to cell membrane hyperpolarization and greater reduction in cytosolic free Ca ([Ca ] ). Decreasing extracellular Ca also reduced basal [DA] , despite increasing firing frequency. Furthermore, inhibiting L-type Ca channels decreased basal [DA] , although specific Ca 1.3 channel inhibition did not affect firing rate. Inhibition of sarcoplasmic/endoplasmic reticulum Ca -ATPase (SERCA) also decreased [DA] , demonstrating the importance of intracellular Ca stores for somatodendritic release. Finally, in vivo FSCAV measurements showed that basal [DA] in the SNc was 79.8 ± 10.9 nM in urethane-anesthetized rats, which was enhanced by amphetamine. Overall, our findings indicate that although tonic somatodendritic DA release is largely independent of action potentials, basal [DA] is strongly regulated by voltage-dependent Ca influx and release of intracellular Ca .

Dopamine neuron-derived IGF-1 controls dopamine neuron firing, skill learning, and exploration

“…S4). These data suggest that spontaneous DA release from the soma is largely independent of action potentials, in agreement with a recent report (32). Treatment with des(1-3)IGF-1 resulted in a slower rate of release of FFN102, indicating that engagement of the IGF-1R pathway by the IGF-1 agonist slows down the release of DA from the cell body (Fig.…”

Calcium, Bioenergetics, and Parkinson’s Disease

“…The autonomous pacemaking of SN DAergic neurons is modulated up and down by synaptic inputs [ 77 ], allowing bidirectional control of DA release, which in turn bidirectionally modulate basal ganglia circuits [ 78 , 79 , 80 ]. SN DAergic neurons also release DA from their somatodendritic membrane [ 81 , 82 , 83 ]. This release is known to modulate synaptic input to neighboring substantia nigra pars reticulata (SNr) GABAergic neurons that form a major portion of the basal ganglia interface with the rest of the brain [ 84 ].…”

Robustness to Axon Initial Segment Variation Is Explained by Somatodendritic Excitability in Rat Substantia Nigra Dopaminergic Neurons

“…First, SNc DA neurons are spontaneously active: their pacemaking pattern of activity is observed both in vitro and in vivo; even though in the latter case, it is modulated by synaptic inputs (Gantz et al, 2018). Second, these neurons are not only releasing DA from their axonal terminals in the striatum but also communicate locally in the SNc via AP-dependent somatodendritic release of DA (Vandecasteele et al, 2008;Yee et al, 2019). These specificities explain why soma-todendritic excitability (via sodium and calcium channels) may be so central to SNc DA neurons, as it supports both the voltage oscillations giving rise to pacemaking activity and the faithful AP back-propagation necessary for somatodendritic release of DA.…”