scholarly journals MORPHOLOGICAL DETERMINANTS OF CELL-TO-CELL VARIATIONS IN ACTION POTENTIAL DYNAMICS IN SUBSTANTIA NIGRA DOPAMINERGIC NEURONS

2021 ◽  
Author(s):  
Estelle Moubarak ◽  
Yanis Inglebert ◽  
Fabien Tell ◽  
Jean-Marc Goaillard

ABSTRACTAction potential (AP) shape is a critical electrophysiological parameter, in particular because it strongly modulates neurotransmitter release. AP shape is also used to distinguish neuronal populations, as it greatly varies between neuronal types. For instance, AP duration ranges from hundreds of microseconds in cerebellar granule cells to 2-3 milliseconds in substantia nigra pars compacta (SNc) dopaminergic (DA) neurons. While most of this variation seems to arise from differences in the subtypes of voltage- and calcium-gated ion channels expressed, a few studies suggested that dendritic morphology may also affect AP shape. However, AP duration also displays significant variability in a same neuronal type, while the determinants of these variations are poorly known. Using electrophysiological recordings, morphological reconstructions and realistic Hodgkin-Huxley modeling, we investigated the relationships between dendritic morphology and AP shape in SNc DA neurons. In this neuronal type where the axon arises from an axon-bearing dendrite (ABD), the duration of the somatic AP could be predicted from a linear combination of the complexities of the ABD and the non-ABDs. Dendrotomy simulation and experiments showed that these correlations arise from the causal influence of dendritic topology on AP duration, due in particular to a high density of sodium channels in the somato-dendritic compartment. In addition, dendritic morphology also modulated AP back-propagation efficiency in response to barrages of EPSCs in the ABD. In line with previous findings, these results demonstrate that dendritic morphology plays a major role in defining the electrophysiological properties of SNc DA neurons and their cell-to-cell variations.SIGNIFICANCE STATEMENTAction potential (AP) shape is a critical electrophysiological parameter, in particular because it strongly modulates neurotransmitter release. AP shape (e.g. duration) greatly varies between neuronal types but also within a same neuronal type. While differences in ion channel expression seem to explain most of AP shape variation across cell types, the determinants of cell-to-cell variations in a same neuronal type are mostly unknown. We used electrophysiological recordings, neuronal reconstruction and modeling to show that, due to the presence of sodium channels in the somato-dendritic compartment, a large part of cell-to-cell variations in somatic AP duration in substantia nigra pars compacta dopaminergic neurons is explained by variations in dendritic topology.

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Daniel J Galtieri ◽  
Chad M Estep ◽  
David L Wokosin ◽  
Stephen Traynelis ◽  
D James Surmeier

Burst spiking in substantia nigra pars compacta (SNc) dopaminergic neurons is a key signaling event in the circuitry controlling goal-directed behavior. It is widely believed that this spiking mode depends upon an interaction between synaptic activation of N-methyl-D-aspartate receptors (NMDARs) and intrinsic oscillatory mechanisms. However, the role of specific neural networks in burst generation has not been defined. To begin filling this gap, SNc glutamatergic synapses arising from pedunculopotine nucleus (PPN) neurons were characterized using optical and electrophysiological approaches. These synapses were localized exclusively on the soma and proximal dendrites, placing them in a good location to influence spike generation. Indeed, optogenetic stimulation of PPN axons reliably evoked spiking in SNc dopaminergic neurons. Moreover, burst stimulation of PPN axons was faithfully followed, even in the presence of NMDAR antagonists. Thus, PPN-evoked burst spiking of SNc dopaminergic neurons in vivo may not only be extrinsically triggered, but extrinsically patterned as well.


2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Valeria V. Goloborshcheva ◽  
Kirill D. Chaprov ◽  
Ekaterina V. Teterina ◽  
Ruslan Ovchinnikov ◽  
Vladimir L. Buchman

2021 ◽  
Author(s):  
Alexis Haddjeri-Hopkins ◽  
Mónica Tapia ◽  
Jorge Ramirez-Franco ◽  
Fabien Tell ◽  
Béatrice Marqueze-Pouey ◽  
...  

ABSTRACTSubstantia nigra pars compacta (SNc) dopaminergic (DA) neurons display a peculiar electrical phenotype characterized in vitro by a spontaneous tonic regular activity (pacemaking activity), a broad action potential and a biphasic post-inhibitory response. Several studies in rodents have underlined the central role played by the transient A-type current (IA) in the control of pacemaking activity and post-inhibitory rebound properties, thereby influencing both DA release and the physiological response of SNc neurons to incoming inhibitory inputs. Kv4.3 potassium channels were considered to be fully responsible for IA in these neurons, their density being tightly related to pacemaking frequency. In spite of this crucial electrophysiological role, we show that Kv4.3-/- transgenic mice exhibit minor alterations in locomotion and motor learning, although no compensation by functionally overlapping ion channels is observed in Kv4.3-/- SNc DA neurons. Using antigen retrieval immunohistochemistry, we further demonstrate that Kv4.2 potassium channels are also expressed in SNc DA neurons, even though their contribution to IA appears significant only in a minority of neurons (~5-10%). Using correlative analysis on recorded electrophysiological parameters and multi-compartment modeling, we then demonstrate that, rather than its conductance level, IA gating kinetics (inactivation time constant) appear as the main biophysical property defining post-inhibitory rebound delay and pacemaking frequency. Moreover, we show that the hyperpolarization-activated current (IH) has an opposing and complementary influence on the same firing features, and that the biophysical properties of IA and IH are likely coregulated in mouse SNc DA neurons.SIGNIFICANCE STATEMENTSubstantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by pacemaking activity, a broad action potential and biphasic post-inhibitory response. The A-type transient potassium current (IA) plays a central role in both pacemaking activity and post-inhibitory response. While it was thought so far that Kv4.3 ion channels were fully responsible for IA, using a Kv4.3-/- transgenic mouse and antigen retrieval immunohistochemistry we demonstrate that Kv4.2 channels are also expressed in SNc DA neurons, although their contribution is significant in a minority of neurons only. Using electrophysiological recordings and computational modeling, we then demonstrate that IA gating kinetics and its functional complementarity with the hyperpolarization-activated current are major determinants of both pacemaking activity and post-inhibitory response in SNc DA neurons.


eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ankita Ravi Vaswani ◽  
Beatrice Weykopf ◽  
Cathleen Hagemann ◽  
Hans-Ulrich Fried ◽  
Oliver Brüstle ◽  
...  

Midbrain dopaminergic (mDA) neurons migrate to form the laterally-located substantia nigra pars compacta (SN) and medially-located ventral tegmental area (VTA), but little is known about the underlying cellular and molecular processes. Here we visualize the dynamic cell morphologies of tangentially migrating SN-mDA neurons in 3D and identify two distinct migration modes. Slow migration is the default mode in SN-mDA neurons, while fast, laterally-directed migration occurs infrequently and is strongly associated with bipolar cell morphology. Tangential migration of SN-mDA neurons is altered in absence of Reelin signaling, but it is unclear whether Reelin acts directly on migrating SN-mDA neurons and how it affects their cell morphology and migratory behavior. By specifically inactivating Reelin signaling in mDA neurons we demonstrate its direct role in SN-mDA tangential migration. Reelin promotes laterally-biased movements in mDA neurons during their slow migration mode, stabilizes leading process morphology and increases the probability of fast, laterally-directed migration.


eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Martial A Dufour ◽  
Adele Woodhouse ◽  
Julien Amendola ◽  
Jean-Marc Goaillard

Neurons have complex electrophysiological properties, however, it is often difficult to determine which properties are the most relevant to neuronal function. By combining current-clamp measurements of electrophysiological properties with multi-variate analysis (hierarchical clustering, principal component analysis), we were able to characterize the postnatal development of substantia nigra dopaminergic neurons' electrical phenotype in an unbiased manner, such that subtle changes in phenotype could be analyzed. We show that the intrinsic electrical phenotype of these neurons follows a non-linear trajectory reaching maturity by postnatal day 14, with two developmental transitions occurring between postnatal days 3–5 and 9–11. This approach also predicted which parameters play a critical role in phenotypic variation, enabling us to determine (using pharmacology, dynamic-clamp) that changes in the leak, sodium and calcium-activated potassium currents are central to these two developmental transitions. This analysis enables an unbiased definition of neuronal type/phenotype that is applicable to a range of research questions.


Author(s):  
В.В. Голоборщева ◽  
Н.А. Воронина ◽  
Р.К. Овчинников ◽  
В.Г. Кучеряну ◽  
С.Г. Морозов

Целью данной работы являлась оценка выживаемости популяции зрелых дофаминергических (ДА-ергических) нейронов чёрной субстанции двух альфа-синуклеин нокаутных линий мышей Abel-KO и ΔFlox-KO, а также бессинуклеиновых животных abg-КО в условиях МФТП-токсического моделирования паркинсонического синдрома. Методы исследования: Водный раствор нейротоксина МФТП вводили 3-месячным мышам внутрибрюшинно в дозе 30 мг/кг ежедневно в течение 5 дней по субхроническому протоколу. Через 21 день после последней инъекции МФТП у животных извлекали головной мозг, фиксировали в холодном растворе Карнуа и парафинизировали для последующего приготовления гистологических препаратов на ротационном микротоме Leica RM2265 (Leica Biosystems, Германия). Иммуногистохимическое окрашивание проводили антителами против тирозингидроксилазы (моноклональные антитела мыши, Sigma, разведение 1:2000). Сравнительный морфометрический анализ популяции ДА-ергических нейронов чёрной субстанции выполнен с учётом поправки Аберкромби. Результаты: Установлено, что в условиях дефицита альфа-синуклеина мыши устойчивы к потере ДА-ергических нейронов в компактной части ЧС после введения МФТП. При генетической делеции всех трёх синуклеинов чувствительность ДА-ергических нейронов ЧС к токсическому действию МФТП не отличается от таковой у животных с немодифицированным геномом. Заключение. На основании проведённого морфометрического анализа предполагается, что особенности чувствительности к нейротоксину МФТП у альфа-синуклеин нокаутных линий мышей обусловлены повышением функциональной активности (замещением) бета-синуклеина, оптимизирующего захват ДА синаптическими везикулами. The aim of this study was to assess survival of mature dopaminergic (DAergic) neuronal population in the substantia nigra pars compacta (SNpc) of two alpha-synuclein knockout mice strains (Abel-KO and ΔFlox-KO) and of non-synuclein animals (abg-KO) in MPTP-induced parkinsonism. Material and methods: MPTP water solution was administered to 3-month-old mice intraperitoneally (30 mg/kg daily for 5 days) according to a subchronic protocol. On the 21st day after the last MPTP injection, the brain was excised, fixed in cold Carnoy’s solution and paraffined for the subsequent preparation of histological samples on a Leica RM2265 rotary microtome (Leica Biosystems, Germany). Immunohistochemical staining was performed with antibodies against tyrosine hydroxylase (mouse monoclonal antibodies, Sigma, dilution 1:2000). A comparative morphometric analysis of substantia nigra dopaminergic neurons was performed using the Abercrombie correction. Results: MPTP-treated alpha-synuclein deficient mice were resistant to the loss of DAergic neurons in the SNpc. Genetic deletion of all three synucleins restored the sensitivity of SNpc DAergic neurons to the MPTP toxicity, which did not differ from the sensitivity of wild type animals. Conclusion: Based on the morphometric analysis, it was assumed that the specific features of MPTP sensitivity in alpha-synuclein knockout mice are due to an increased functional activity (substitution) of beta-synuclein, which optimizes the capture of DA by synaptic vesicles.


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