Publications by authors named "Jean-Marc Goaillard"

27 Publications

  • Page 1 of 1

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

Annu Rev Neurosci 2021 Mar 26. Epub 2021 Mar 26.

Volen Center and Department of Biology, Brandeis University, Waltham, Massachusetts 02454, USA; email:

The 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. Expected final online publication date for the , Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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http://dx.doi.org/10.1146/annurev-neuro-092920-121538DOI Listing
March 2021

Diversity of Axonal and Dendritic Contributions to Neuronal Output.

Front Cell Neurosci 2019 22;13:570. Epub 2020 Jan 22.

UMR_S 1072, Aix Marseille Université, INSERM, Faculté de Médecine Secteur Nord, Marseille, France.

Our 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.
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http://dx.doi.org/10.3389/fncel.2019.00570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987044PMC
January 2020

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

J Neurosci 2019 06 26;39(26):5044-5063. Epub 2019 Apr 26.

Unité Mixte de Recherche_S 1072, Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Secteur Nord, 13015 Marseille, France, and

In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. Interestingly, the axon of rat SNc dopaminergic (DA) neurons displays a highly variable location and most often arises from an axon-bearing dendrite (ABD). We combined current-clamp somatic and dendritic recordings, outside-out recordings of dendritic sodium and potassium currents, morphological reconstructions and multicompartment modeling on male and female rat SNc DA neurons to determine cell-to-cell variations in AIS and ABD geometry, and their influence on neuronal output (spontaneous pacemaking frequency, action potential [AP] shape). Both AIS and ABD geometries were found to be highly variable from neuron to neuron. Surprisingly, we found that AP shape and pacemaking frequency were independent of AIS geometry. Modeling realistic morphological and biophysical variations helped us clarify this result: in SNc DA neurons, the complexity of the ABD combined with its excitability predominantly define pacemaking frequency and AP shape, such that large variations in AIS geometry negligibly affect neuronal output and are tolerated. In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. In the current study, we describe large cell-to-cell variations in AIS length or distance from the soma in rat substantia nigra pars compacta dopaminergic neurons. Using neuronal reconstruction and electrophysiological recordings, we show that this morphological variability does not seem to affect their electrophysiological output, as neither action potential properties nor pacemaking frequency is correlated with AIS morphology. Realistic multicompartment modeling suggests that this robustness to AIS variation is mainly explained by the complexity and excitability of the somatodendritic compartment.
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http://dx.doi.org/10.1523/JNEUROSCI.2781-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595954PMC
June 2019

Neurotransmitter identity and electrophysiological phenotype are genetically coupled in midbrain dopaminergic neurons.

Sci Rep 2018 09 11;8(1):13637. Epub 2018 Sep 11.

Unité de Neurobiologie des Canaux Ioniques et de la Synapse, INSERM UMR 1072, Aix Marseille Université, 13015, Marseille, France.

Most neuronal types have a well-identified electrical phenotype. It is now admitted that a same phenotype can be produced using multiple biophysical solutions defined by ion channel expression levels. This argues that systems-level approaches are necessary to understand electrical phenotype genesis and stability. Midbrain dopaminergic (DA) neurons, although quite heterogeneous, exhibit a characteristic electrical phenotype. However, the quantitative genetic principles underlying this conserved phenotype remain unknown. Here we investigated the quantitative relationships between ion channels' gene expression levels in midbrain DA neurons using single-cell microfluidic qPCR. Using multivariate mutual information analysis to decipher high-dimensional statistical dependences, we unravel co-varying gene modules that link neurotransmitter identity and electrical phenotype. We also identify new segregating gene modules underlying the diversity of this neuronal population. We propose that the newly identified genetic coupling between neurotransmitter identity and ion channels may play a homeostatic role in maintaining the electrophysiological phenotype of midbrain DA neurons.
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http://dx.doi.org/10.1038/s41598-018-31765-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134142PMC
September 2018

Non-linear developmental trajectory of electrical phenotype in rat substantia nigra pars compacta dopaminergic neurons.

Elife 2014 Oct 20;3. Epub 2014 Oct 20.

Inserm UMR 1072, Faculté de Médecine Secteur Nord, Université de la Méditerranée, Marseille, France.

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.
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http://dx.doi.org/10.7554/eLife.04059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241557PMC
October 2014

Physiological epidermal growth factor concentrations activate high affinity receptors to elicit calcium oscillations.

PLoS One 2014 29;9(9):e106803. Epub 2014 Sep 29.

Centre d'Immunologie de Marseille-Luminy, UM2 Aix Marseille Université, Marseille, France; INSERM, U1104, Marseille, France; CNRS, UMR7280, Marseille, France.

Signaling 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 Ca2+ 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 Ca2+ indicator, we found that picomolar concentrations of EGF induced in 50% of the cells a robust oscillatory Ca2+ signal quantitatively similar to the Ca2+ 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 Ca2+ channels that are not activated by internal Ca2+ store depletion, while the nanomolar EGF response involved internal Ca2+ 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179260PMC
June 2015

AaTX1, from Androctonus australis scorpion venom: purification, synthesis and characterization in dopaminergic neurons.

Toxicon 2014 Dec 18;92:14-23. Epub 2014 Sep 18.

Institut Pasteur de Tunis, Laboratoire des Venins et biomolécules thérapeutiques LR11IPT08, Tunis 1002, Tunisia. Electronic address:

We have purified the AaTX1 peptide from the Androctonus australis (Aa) scorpion venom, previously cloned and sequenced by Legros and collaborators in a venom gland cDNA library from Aa scorpion. AaTX1 belongs to the α-Ktx15 scorpion toxins family (αKTx15-4). Characterized members of this family share high sequence similarity and were found to block preferentially IA-type voltage-dependent K(+) currents in rat cerebellum granular cells in an irreversible way. In the current work, we studied the effects of native AaTX1 (nAaTX1) using whole-cell patch-clamp recordings of IA current in substantia nigra pars compacta dopaminergic neurons. At 250 nM, AaTX1 induces 90% decrease in IA current amplitude. Its activity was found to be comparable to that of rAmmTX3 (αKTx15-3), which differs by only one conserved (R/K) amino acid in the 19th position suggesting that the difference between R19 and K19 in AaTX1 and AmmTX3, respectively, may not be critical for the toxins' effects. Molecular docking of both toxins with Kv4.3 channel is in agreement with experimental data and suggests the implication of the functional dyade K27-Y36 in toxin-channel interactions. Since AaTX1 is not highly abundant in Aa venom, it was synthesized as well as AmmTX3. Synthetic peptides, native AaTX1 and rAmmTX3 peptides showed qualitatively the same pharmacological activity. Overall, these data identify a new biologically active toxin that belongs to a family of peptides active on Kv4.3 channel.
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http://dx.doi.org/10.1016/j.toxicon.2014.09.005DOI Listing
December 2014

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

J Neurosci Res 2014 Aug 10;92(8):981-99. Epub 2014 Apr 10.

INSERM, UMR_S 1072, 13015, Marseille, France; Aix-Marseille Université, UNIS, 13015, Marseille, France.

Dopaminergic 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.
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http://dx.doi.org/10.1002/jnr.23382DOI Listing
August 2014

The pros and cons of degeneracy.

Elife 2014 Apr 1;3:e02615. Epub 2014 Apr 1.

Jean-Marc Goaillard is at Inserm (Inserm UMR_S 1072) and Aix Marseille University, Marseille, France

Drugs could treat neuropathic pain more effectively if they simultaneously targeted two or more types of ion channel.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970757PMC
http://dx.doi.org/10.7554/eLife.02615DOI Listing
April 2014

The 22nd ion channel meeting, september 2011, france.

Channels (Austin) 2012 May-Jun;6(3):149-53. Epub 2012 May 1.

Neurobiologie des Canaux Ioniques, INSERM-Université de la Méditerranée, Marseille, France.

The 22(nd) Ion Channel Meeting was organized by the French Ion Channel Society (Association Canaux Ioniques) from the 25(th) to the 28(th) of September 2011 on the French Riviera (Giens). This year again, more than one hundred researchers from France, Europe and extra-European countries gathered to present and discuss their recent advances and future challenges in the ion channels and transporters field. The scientific committee organized a plenary lecture and five thematic symposia by inviting international researchers to present their recent outstanding work on themes as diverse as muscular channelopathies, regulation of channels by extracellular matrix, receptor-channels interactions, localization and distribution of ion channels, their involvement in the cell life and death, and finally how they participate in the evolution and adaptability of cellular excitability. These presentations are summarized in this meeting report. Two sessions of oral communications selected from submitted abstracts and two poster sessions were also organized to present the ongoing work of young researchers worldwide.
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http://dx.doi.org/10.4161/chan.20795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431583PMC
December 2012

Ca²⁺/cAMP-sensitive covariation of I(A) and I(H) voltage dependences tunes rebound firing in dopaminergic neurons.

J Neurosci 2012 Feb;32(6):2166-81

Institut National de la Santé et de la Recherche Médicale UMR1072, Marseille 13015, France.

The level of expression of ion channels has been demonstrated to vary over a threefold to fourfold range from neuron to neuron, although the expression of distinct channels may be strongly correlated in the same neurons. We demonstrate that variability and covariation also apply to the biophysical properties of ion channels. We show that, in rat substantia nigra pars compacta dopaminergic neurons, the voltage dependences of the A-type (I(A)) and H-type (I(H)) currents exhibit a high degree of cell-to-cell variability, although they are strongly correlated in these cells. Our data also demonstrate that this cell-to-cell covariability of voltage dependences is sensitive to cytosolic cAMP and calcium levels. Finally, using dynamic clamp, we demonstrate that covarying I(A) and I(H) voltage dependences increases the dynamic range of rebound firing while covarying their amplitudes has a homeostatic effect on rebound firing. We propose that the covariation of voltage dependences of ion channels represents a flexible and energy-efficient way of tuning firing in neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.5297-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621702PMC
February 2012

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

Prog Neurobiol 2011 Sep 17;94(4):307-46. Epub 2011 Jun 17.

The Whitney Laboratory and Department of Neuroscience, University of Florida, St. Augustine, FL 32080, USA.

Most 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.
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http://dx.doi.org/10.1016/j.pneurobio.2011.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156869PMC
September 2011

Neural networks: more about flexibility than synaptic strength.

Curr Biol 2011 Apr;21(8):R276-8

INSERM U641, Marseille, 13916, France, and Université de la Méditerranée, Faculté de Médecine Secteur Nord, IFR11, Marseille, 13916, France.

The leech heartbeat neural network is famous for its constancy in both architecture and functional output across animals. A recent study, however, has found that the synaptic strengths underlying this constancy are quite variable across animals.
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http://dx.doi.org/10.1016/j.cub.2011.03.004DOI Listing
April 2011

Slow and persistent postinhibitory rebound acts as an intrinsic short-term memory mechanism.

J Neurosci 2010 Mar;30(13):4687-92

Volen Center for Complex Systems and Biology Department, Brandeis University, Waltham, Massachusetts 02454, USA.

Many neurons exhibit postinhibitory rebound (PIR), in which neurons display enhanced excitability following inhibition. PIR can strongly influence the timing of spikes on rebound from an inhibitory input. We studied PIR in the lateral pyloric (LP) neuron of the stomatogastric ganglion of the crab Cancer borealis. The LP neuron is part of the pyloric network, a central pattern generator that normally oscillates with a period of approximately 1 s. We used the dynamic clamp to create artificial rhythmic synaptic inputs of various periods and duty cycles in the LP neuron. Surprisingly, we found that the strength of PIR increased slowly over multiple cycles of synaptic input. Moreover, this increased excitability persisted for 10-20 s after the rhythmic inhibition was removed. These effects are considerably slower than the rhythmic activity typically observed in LP. Thus this slow postinhibitory rebound allows the neuron to adjust its level of excitability to the average level of inhibition over many cycles, and is another example of an intrinsic "short-term memory" mechanism.
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http://dx.doi.org/10.1523/JNEUROSCI.2998-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885135PMC
March 2010

Immature brains don't need GABA to get 'hyper'-excited.

J Physiol 2010 Jan;588(Pt 1):7-8

INSERM U641, Marseille, 13916 France.

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http://dx.doi.org/10.1113/jphysiol.2009.183905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821534PMC
January 2010

Functional consequences of animal-to-animal variation in circuit parameters.

Nat Neurosci 2009 Nov 18;12(11):1424-30. Epub 2009 Oct 18.

Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts, USA.

How different are the neuronal circuits for a given behavior across individual animals? To address this question, we measured multiple cellular and synaptic parameters in individual preparations to see how they correlated with circuit function, using neurons and synapses in the pyloric circuit of the stomatogastric ganglion of the crab Cancer borealis. There was considerable preparation-to-preparation variability in the strength of two identified synapses, in the amplitude of a modulator-evoked current and in the expression of six ion channel genes. Nonetheless, we found strong correlations across preparations among these parameters and attributes of circuit performance. These data illustrate the importance of making multidimensional measurements from single preparations for understanding how variability in circuit output is related to the variability of multiple circuit parameters.
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http://dx.doi.org/10.1038/nn.2404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826985PMC
November 2009

How multiple conductances determine electrophysiological properties in a multicompartment model.

J Neurosci 2009 Apr;29(17):5573-86

Volen Center, Brandeis University, Waltham, Massachusetts 02454, USA.

Most neurons have large numbers of voltage- and time-dependent currents that contribute to their electrical firing patterns. Because these currents are nonlinear, it can be difficult to determine the role each current plays in determining how a neuron fires. The lateral pyloric (LP) neuron of the stomatogastric ganglion of decapod crustaceans has been studied extensively biophysically. We constructed approximately 600,000 versions of a four-compartment model of the LP neuron and distributed 11 different currents into the compartments. From these, we selected approximately 1300 models that match well the electrophysiological properties of the biological neuron. Interestingly, correlations that were seen in the expression of channel mRNA in biological studies were not found across the approximately 1300 admissible LP neuron models, suggesting that the electrical phenotype does not require these correlations. We used cubic fits of the function from maximal conductances to a series of electrophysiological properties to ask which conductances predominantly influence input conductance, resting membrane potential, resting spike rate, phasing of activity in response to rhythmic inhibition, and several other properties. In all cases, multiple conductances contribute to the measured property, and the combinations of currents that strongly influence each property differ. These methods can be used to understand how multiple currents in any candidate neuron interact to determine the cell's electrophysiological behavior.
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http://dx.doi.org/10.1523/JNEUROSCI.4438-08.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821064PMC
April 2009

Quantitative expression profiling of identified neurons reveals cell-specific constraints on highly variable levels of gene expression.

Proc Natl Acad Sci U S A 2007 Aug 25;104(32):13187-91. Epub 2007 Jul 25.

Biological Sciences, 218A LeFevre Hall, University of Missouri, Columbia, MO 65211, USA.

The postdevelopmental basis of cellular identity and the unique cellular output of a particular neuron type are of particular interest in the nervous system because a detailed understanding of circuits responsible for complex processes in the brain is impeded by the often ambiguous classification of neurons in these circuits. Neurons have been classified by morphological, electrophysiological, and neurochemical techniques. More recently, molecular approaches, particularly microarray, have been applied to the question of neuronal identity. With the realization that proteins expressed exclusively in only one type of neuron are rare, expression profiles obtained from neuronal subtypes are analyzed to search for diagnostic patterns of gene expression. However, this expression profiling hinges on one critical and implicit assumption: that neurons of the same type in different animals achieve their conserved functional output via conserved levels and quantitative relationships of gene expression. Here we exploit the unambiguously identifiable neurons in the crab stomatogastric ganglion to investigate the precise quantitative expression profiling of neurons at the level of single-cell ion channel expression. By measuring absolute mRNA levels of six different channels in the same individually identified neurons, we demonstrate that not only do individual cell types possess highly variable levels of channel expression but that this variability is constrained by unique patterns of correlated channel expression.
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http://dx.doi.org/10.1073/pnas.0705827104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933263PMC
August 2007

Variability, compensation and homeostasis in neuron and network function.

Nat Rev Neurosci 2006 Jul;7(7):563-74

Volen Center and Biology Department, MS 013 Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA.

Neurons in most animals live a very long time relative to the half-lives of all of the proteins that govern excitability and synaptic transmission. Consequently, homeostatic mechanisms are necessary to ensure stable neuronal and network function over an animal's lifetime. To understand how these homeostatic mechanisms might function, it is crucial to understand how tightly regulated synaptic and intrinsic properties must be for adequate network performance, and the extent to which compensatory mechanisms allow for multiple solutions to the production of similar behaviour. Here, we use examples from theoretical and experimental studies of invertebrates and vertebrates to explore several issues relevant to understanding the precision of tuning of synaptic and intrinsic currents for the operation of functional neuronal circuits.
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http://dx.doi.org/10.1038/nrn1949DOI Listing
July 2006

Dynamic clamp analyses of cardiac, endocrine, and neural function.

Physiology (Bethesda) 2006 Jun;21:197-207

Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts, USA.

The dynamic clamp introduces artificial conductances into cells to simulate electrical coupling, votage-dependent, leak, and synaptic conductances. This review describes how the dynamic clamp has been used to address various questions in the cardiac, endocrine, and nervous systems.
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http://dx.doi.org/10.1152/physiol.00063.2005DOI Listing
June 2006

Variable channel expression in identified single and electrically coupled neurons in different animals.

Nat Neurosci 2006 Mar 29;9(3):356-62. Epub 2006 Jan 29.

Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts 02454, USA.

It is often assumed that all neurons of the same cell type have identical intrinsic properties, both within an animal and between animals. We exploited the large size and small number of unambiguously identifiable neurons in the crab stomatogastric ganglion to test this assumption at the level of channel mRNA expression and membrane currents (measured in voltage-clamp experiments). In lateral pyloric (LP) neurons, we saw strong correlations between measured current and the abundance of Shal and BK-KCa mRNAs (encoding the Shal-family voltage-gated potassium channel and large-conductance calcium-activated potassium channel, respectively). We also saw two- to fourfold interanimal variability for three potassium currents and their mRNA expression. Measurements of channel expression in the two electrically coupled pyloric dilator (PD) neurons showed significant interanimal variability, but copy numbers for IH (encoding the hyperpolarization-activated, inward-current channel) and Shal mRNA in the two PD neurons from the same crab were similar, suggesting that the regulation of some currents may be shared in electrically coupled neurons.
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http://dx.doi.org/10.1038/nn1639DOI Listing
March 2006

Bistable behavior originating in the axon of a crustacean motor neuron.

J Neurophysiol 2006 Mar 16;95(3):1356-68. Epub 2005 Nov 16.

Department of Physics, Santa Clara University, Santa Clara, CA 95053-0315, USA.

Both vertebrate and invertebrate motor neurons can display bistable behavior in which self-sustained tonic firing results from a brief excitatory stimulus. Induction of the bistability is usually dependent on activation of intrinsic conductances located in the somatodendritic area and is commonly sensitive to action of neuromodulators. We have observed bistable behavior in a neuromuscular preparation from the foregut of the crab Cancer borealis that consists of the gastric mill 4 (gm4) muscle and the nerve that innervates it, the dorsal gastric nerve (dgn). Nerve-evoked contractions of enhanced amplitude and long duration (>30 s) were induced by extracellular stimulation when the stimulus voltage was above a certain threshold. Intracellular and extracellular recordings showed that the large contractions were accompanied by persistent firing of the dorsal gastric (DG) motor neuron that innervates gm4. The persistent firing could be induced only by stimulating a specific region of the axon and could not be triggered by depolarizing the soma, even at current amplitudes that induced high-frequency firing of the neuron. The bistable behavior was abolished in low-Ca2+ saline or when nicardipine or flufenamic acid, blockers of L-type Ca2+ and Ca2+-activated nonselective cation currents, respectively, was applied to the axonal stimulation region of the dgn. Negative immunostaining for synapsin and synaptotagmin argued against the presence of synaptic/modulatory neuropil in the dgn. Collectively, our results suggest that bistable behavior in a motor neuron can originate in the axon and may not require the action of a locally released neuromodulator.
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http://dx.doi.org/10.1152/jn.00893.2005DOI Listing
March 2006

Octopamine modulates the axons of modulatory projection neurons.

J Neurosci 2004 Aug;24(32):7063-73

Volen Center and Biology Department, Brandeis University, Waltham, Massachusetts 02454, USA.

Octopamine increases the cycle frequency of the pyloric rhythm in the crab Cancer borealis by acting at multiple sites within the stomatogastric nervous system. The junction between the stomatogastric nerve (stn) and the superior esophageal nerve (son) shows synaptic structures. When applied only to the stn-son junction, octopamine induced action potentials in the axons of the modulatory commissural neuron 5 (MCN5) that project from the commissural ganglia to the stomatogastric ganglion (STG). The activation of the MCN5 neurons was correlated with an increase in the pyloric rhythm frequency. Additionally, octopamine had direct effects on the STG, including the activation of the pyloric dilator and pyloric neurons, an increase in the pyloric frequency, and a change in the phase relationships of the pyloric neurons. Thus, the same modulator can influence the pyloric rhythm by acting at multiple sites, including the axons of identified modulatory neurons that project to the STG. These data demonstrate that axonal propagation may be influenced locally by neuromodulators acting on axonal receptors, therefore altering the conduction of information from different command and integrating centers.
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http://dx.doi.org/10.1523/JNEUROSCI.2078-04.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729165PMC
August 2004

Exciting guts with GABA.

Nat Neurosci 2003 Nov;6(11):1121-2

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http://dx.doi.org/10.1038/nn1103-1121DOI Listing
November 2003

Serotonin suppresses the slow afterhyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT(7) receptors.

J Physiol 2002 Jun;541(Pt 2):453-65

Equipe Neurobiologie Cellulaire, Neurobiologie des Processus Adaptatifs UMR 7102, CNRS Université Paris VI, F-75005 Paris, France.

While the highest expression level of 5-HT(7) receptors in the brain is observed in intralaminar and midline thalamic neurones, the physiological role of these receptors in this structure is unknown. In vivo recordings have shown that stimulation of the serotonergic raphe nuclei can alter the response of these neurones to a nociceptive stimulus, suggesting that serotonin modulates their firing properties. Using the patch-clamp technique in rat thalamic brain slices, we demonstrate that activation of 5-HT(7) receptors can strongly modulate the excitability of intralaminar and midline thalamic neurones by inhibiting the calcium-activated potassium conductance that is responsible for the slow afterhyperpolarization (sAHP) following a spike discharge. This sAHP was inhibited after activation of the cAMP pathway, either by bath application of forskolin or intracellular perfusion with 8-bromo-cAMP. The inhibitory effect of 5-HT(7) receptors on sAHPs was blocked by the protein kinase A antagonist R(P)-cAMPS. Calcium-imaging experiments showed no change in intracellular calcium levels during the 5-HT(7) response, indicating that in these neurones, a global calcium signal was not necessary to activate the cAMP cascade. Finally, bath application of serotonin produced a strong increase in cytosolic cAMP concentration, as measured using the fluorescent probe FlCRhR, and an inhibition of the sAHP. Taken together, these results suggest that 5-HT(7) receptors are implicated in the effect of 5-HT on sAHP in intralaminar and midline thalamic neurones, an effect that is mediated by the cAMP second-messenger cascade.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290335PMC
http://dx.doi.org/10.1113/jphysiol.2001.013896DOI Listing
June 2002

Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice.

J Neurosci 2002 Feb;22(3):886-900

Laboratoire de Neurophysiologie et Nouvelles Microscopies, Institut National de la Santé et de la Recherche Médicale (INSERM) EPI-0002, Ecole Supérieure de Physique et de Chimie Industrielle, 75231 Paris cedex 5, France,

The disruptive effect of excessive serotonin (5-HT) levels on the development of cortical sensory maps is mediated by 5-HT1B receptors, as shown in barrelless monoamine oxidase A knock-out mice, in which the additional inactivation of 5-HT1B receptors restores the barrels. However, it is unclear whether 5-HT1B receptors mediate their effect on barrel formation by a trophic action or an activity-dependent effect. To test for a possible effect of 5-HT1B receptors on activity, we studied the influence of 5-HT on the thalamocortical (TC) synaptic transmission in layer IV cortical neurons. In TC slices of postnatal day 5 (P5)-P9 neonate mice, we show that 5-HT reduces monosynaptic TC EPSCs evoked by low-frequency internal capsule stimulation and relieves the short-term depression of the EPSC evoked by high-frequency stimulation. We provide evidence that 5-HT decreases the presynaptic release of glutamate: 5-HT reduces similarly the AMPA-kainate and NMDA components and the paired pulse depression of TC EPSCs. We show also that 5-HT1B receptors mediate exclusively the effect of 5-HT: first, the effect of 5-HT on the TC EPSC is correlated with the transient expression of 5-HT1B receptor mRNAs in the ventrobasal thalamic nucleus during postnatal development; second, it is mimicked by a 5-HT1B agonist; third, 5-HT has no effect in 5-HT1B receptor knock-out mice. Our results show that in the developing barrel field of the neonatal mice, 5-HT1B receptors mediate an activity-dependent regulation of the TC EPSC that could favor the propagation of high-frequency TC activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758531PMC
February 2002