Physiological Epidermal Growth Factor Concentrations Activate High Affinity Receptors to Elicit Calcium Oscillations

International audienceSignaling mediated by the epidermal growth factor (EGF) is crucial in tissue development, homeostasis and tumorigenesis. EGF is mitogenic at picomolar concentrations and is known to bind its receptor on high affinity binding sites depending of the oligomerization state of the receptor (monomer or dimer). In spite of these observations, the cellular response induced by EGF has been mainly characterized for nanomolar concentrations of the growth factor, and a clear definition of the cellular response to circulating (picomolar) concentrations is still lacking. We investigated Ca 2+ signaling, an early event in EGF responses, in response to picomolar doses in COS-7 cells where the monomer/dimer equilibrium is unaltered by the synthesis of exogenous EGFR. Using the fluo5F Ca 2+ indicator, we found that picomolar concentrations of EGF induced in 50% of the cells a robust oscillatory Ca 2+ signal quantitatively similar to the Ca 2+ signal induced by nanomolar concentrations. However, responses to nanomolar and picomolar concentrations differed in their underlying mechanisms as the picomolar EGF response involved essentially plasma membrane Ca 2+ channels that are not activated by internal Ca 2+ store depletion, while the nanomolar EGF response involved internal Ca 2+ release. Moreover, while the picomolar EGF response was modulated by charybdotoxin-sensitive K + channels, the nanomolar response was insensitive to the blockade of these ion channels

Neural Networks: More about Flexibility Than Synaptic Strength

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Beyond faithful conduction: Short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon

International audienceMost spiking neurons are divided into functional compartments: a dendritic input region, a soma, a site of action potential initiation, an axon trunk and its collaterals for propagation of action potentials, and distal arborizations and terminals carrying the output synapses. The axon trunk and lower order branches are probably the most neglected and are often assumed to do nothing more than faithfully conducting action potentials. Nevertheless, there are numerous reports of complex membrane properties in non-synaptic axonal regions, owing to the presence of a multitude of different ion channels. Many different types of sodium and potassium channels have been described in axons, as well as calcium transients and hyperpolarization-activated inward currents. The complex time- and voltage-dependence resulting from the properties of ion channels can lead to activity-dependent changes in spike shape and resting potential, affecting the temporal fidelity of spike conduction. Neural coding can be altered by activity-dependent changes in conduction velocity, spike failures, and ectopic spike initiation. This is true under normal physiological conditions, and relevant for a number of neuropathies that lead to abnormal excitability. In addition, a growing number of studies show that the axon trunk can express receptors to glutamate, GABA, acetylcholine or biogenic amines, changing the relative contribution of some channels to axonal excitability and therefore rendering the contribution of this compartment to neural coding conditional on the presence of neuromodulators. Long-term regulatory processes, both during development and in the context of activity-dependent plasticity may also affect axonal properties to an underappreciated extent

Étude de la modulation de conductances intrinsèques par la voie de l'adenosine monophosphate cyclique dans deux types de cellules excitables (action du récepteur beta2-adrénergique dans les cardiomyocytes ventriculaires de grenouille et du récepteur 5-HT7 dans les neurones intralaminaires thalamiques de rat)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Ion Channel Degeneracy, Variability, and Covariation in Neuron and Circuit Resilience

International audienceThe large number of ion channels found in all nervous systems poses fundamental questions concerning how the characteristic intrinsic properties of single neurons are determined by the specific subsets of channels they express. All neurons display many different ion channels with overlapping voltage- and time-dependent properties. We speculate that these overlapping properties promote resilience in neuronal function. Individual neurons of the same cell type show variability in ion channel conductance densities even though they can generate reliable and similar behavior. This complicates a simple assignment of function to any conductance and is associated with variable responses of neurons of the same cell type to perturbations, deletions, and pharmacological manipulation. Ion channel genes often show strong positively correlated expression, which may result from the molecular and developmental rules that determine which ion channels are expressed in a given cell type

Somatodendritic ion channel expression in substantia nigra pars compacta dopaminergic neurons across postnatal development

International audienceDopaminergic neurons of the substantia nigra pars compacta (SNc) are involved in the control of movement, sleep, reward, learning, and nervous system disorders and disease. To date, a thorough characterization of the ion channel phenotype of this important neuronal population is lacking. Using immunohistochemistry, we analyzed the somatodendritic expression of voltage-gated ion channel subunits that are involved in pacemaking activity in SNc dopaminergic neurons in 6-, 21-, and 40-day-old rats. Our results demonstrate that the same complement of somatodendritic ion channels is present in SNc dopaminergic neurons from P6 to P40. The major developmental changes were an increase in the dendritic range of the immunolabeling for the HCN, T-type calcium, Kv4.3, delayed rectifier, and SK channels. Our study sheds light on the ion channel subunits that contribute to the somatodendritic delayed rectifier (Kv1.3, Kv2.1, Kv3.2, Kv3.3), A-type (Kv4.3) and calcium-activated SK (SK1, SK2, SK3) potassium currents, IH (mainly HCN2, HCN4), and the L- (Cav1.2, Cav1.3) and T-type (mainly Cav3.1, Cav3.3) calcium currents in SNc dopaminergic neurons. Finally, no robust differences in voltage-gated ion channel immunolabeling were observed across the population of SNc dopaminergic neurons for each age examined, suggesting that differing levels of individual ion channels are unlikely to distinguish between specific subpopulations of SNc dopaminergic neurons. This is significant in light of previous studies suggesting that age- or region-associated variations in the expression profile of voltage-gated ion channels in SNc dopaminergic neurons may underlie their vulnerability to dysfunction and disease

Topological Information Data Analysis

International audienceThis paper presents methods that quantify the structure of statistical interactions within a given data set, and were applied in a previous article. It establishes new results on the k-multivariate mutual-information (I k) inspired by the topological formulation of Information introduced in a serie of studies. In particular, we show that the vanishing of all I k for 2 ≤ k ≤ n of n random variables is equivalent to their statistical independence. Pursuing the work of Hu Kuo Ting and Te Sun Han, we show that information functions provide coordinates for binary variables, and that they are analytically independent from the probability simplex for any set of finite variables. The maximal positive I k identifies the variables that co-vary the most in the population, whereas the minimal negative I k identifies synergistic clusters and the variables that differentiate-segregate the most in the population. Finite data size effects and estimation biases severely constrain the effective computation of the information topology on data, and we provide simple statistical tests for the undersampling bias and the k-dependences. We give an example of application of these methods to genetic expression and unsupervised cell-type classification. The methods unravel biologically relevant subtypes, with a sample size of 41 genes and with few errors. It establishes generic basic methods to quantify the epigenetic information storage and a unified epigenetic unsupervised learning formalism. We propose that higher-order statistical interactions and non-identically distributed variables are constitutive characteristics of biological systems that should be estimated in order to unravel their significant statistical structure and diversity. The topological information data analysis presented here allows for precisely estimating this higher-order structure characteristic of biological systems. "When you use the word information, you should rather use the word form"-René Tho

Diversity of Axonal and Dendritic Contributions to Neuronal Output

International audienceOur general understanding of neuronal function is that dendrites receive information that is transmitted to the axon, where action potentials (APs) are initiated and propagated to eventually trigger neurotransmitter release at synaptic terminals. Even though this canonical division of labor is true for a number of neuronal types in the mammalian brain (including neocortical and hippocampal pyramidal neurons or cerebellar Purkinje neurons), many neuronal types do not comply with this classical polarity scheme. In fact, dendrites can be the site of AP initiation and propagation, and even neurotransmitter release. In several interneuron types, all functions are carried out by dendrites as these neurons are devoid of a canonical axon. In this article, we present a few examples of "misbehaving" neurons (with a non-canonical polarity scheme) to highlight the diversity of solutions that are used by mammalian neurons to transmit information. Moreover, we discuss how the contribution of dendrites and axons to neuronal excitability may impose constraints on the morphology of these compartments in specific functional contexts

NON-LINEAR DEVELOPMENTAL TRAJECTORY OF ELECTRICAL PHENOTYPE IN RAT SUBSTANTIA NIGRA PARS COMPACTA DOPAMINERGIC NEURONS

International audienceNeurons 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

Morphological Determinants of Cell-to-Cell Variations in Action Potential Dynamics in Substantia Nigra Dopaminergic Neurons

International audienceAction potential (AP) shape is a critical electrophysiological parameter, in particular because it strongly modulates neurotransmitter release. As it greatly varies between neuronal types, AP shape is also used to distinguish neuronal populations. For instance, AP duration ranges from hundreds of microseconds in cerebellar granule cells to 2-3 ms in SNc dopaminergic (DA) neurons. While most of this variation across cell types seems to arise from differences in the voltage- and calcium-gated ion channels expressed, a few studies suggested that dendritic morphology also affects AP shape. AP duration also displays significant variability in a same neuronal type, although 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 rat SNc DA neurons from both sexes. 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 ABD and non-ABDs' complexities. Dendrotomy experiments and simulation 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 somatodendritic compartment. Surprisingly, computational modeling suggested that this effect arises from the influence of sodium currents on the decaying phase of the AP. Consistent 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 STATEMENT Action 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, because of the presence of sodium channels in the somatodendritic 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