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1.
Annu Rev Neurosci ; 44: 335-357, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-33770451

RESUMEN

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.


Asunto(s)
Canales Iónicos , Neuronas
2.
J Neurosci ; 42(40): 7530-7546, 2022 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-36658458

RESUMEN

Action 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.


Asunto(s)
Neuronas Dopaminérgicas , Sustancia Negra , Masculino , Femenino , Ratas , Animales , Neuronas Dopaminérgicas/fisiología , Potenciales de Acción/fisiología , Sustancia Negra/fisiología , Canales de Calcio/metabolismo , Canales de Sodio/metabolismo , Neurotransmisores/metabolismo
3.
J Neurosci ; 39(26): 5044-5063, 2019 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-31028116

RESUMEN

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.SIGNIFICANCE STATEMENT 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.


Asunto(s)
Potenciales de Acción/fisiología , Segmento Inicial del Axón/fisiología , Neuronas Dopaminérgicas/fisiología , Sustancia Negra/fisiología , Animales , Axones/fisiología , Dendritas/fisiología , Femenino , Masculino , Modelos Neurológicos , Ratas
4.
J Neurosci Res ; 92(8): 981-99, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24723263

RESUMEN

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.


Asunto(s)
Canales de Calcio/metabolismo , Dendritas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Porción Compacta de la Sustancia Negra/metabolismo , Canales de Potasio/metabolismo , Animales , Porción Compacta de la Sustancia Negra/crecimiento & desarrollo , Ratas , Ratas Wistar
5.
Cells ; 13(11)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38891076

RESUMEN

Pacemaking activity in substantia nigra dopaminergic neurons is generated by the coordinated activity of a variety of distinct somatodendritic voltage- and calcium-gated ion channels. We investigated whether these functional interactions could arise from a common localization in macromolecular complexes where physical proximity would allow for efficient interaction and co-regulations. For that purpose, we immunopurified six ion channel proteins involved in substantia nigra neuron autonomous firing to identify their molecular interactions. The ion channels chosen as bait were Cav1.2, Cav1.3, HCN2, HCN4, Kv4.3, and SK3 channel proteins, and the methods chosen to determine interactions were co-immunoprecipitation analyzed through immunoblot and mass spectrometry as well as proximity ligation assay. A macromolecular complex composed of Cav1.3, HCN, and SK3 channels was unraveled. In addition, novel potential interactions between SK3 channels and sclerosis tuberous complex (Tsc) proteins, inhibitors of mTOR, and between HCN4 channels and the pro-degenerative protein Sarm1 were uncovered. In order to demonstrate the presence of these molecular interactions in situ, we used proximity ligation assay (PLA) imaging on midbrain slices containing the substantia nigra, and we could ascertain the presence of these protein complexes specifically in substantia nigra dopaminergic neurons. Based on the complementary functional role of the ion channels in the macromolecular complex identified, these results suggest that such tight interactions could partly underly the robustness of pacemaking in dopaminergic neurons.


Asunto(s)
Neuronas Dopaminérgicas , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Mesencéfalo , Proteómica , Canales de Potasio de Pequeña Conductancia Activados por el Calcio , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Proteómica/métodos , Neuronas Dopaminérgicas/metabolismo , Animales , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Mesencéfalo/metabolismo , Humanos , Canales de Calcio Tipo L/metabolismo , Ratones , Sustancia Negra/metabolismo
6.
J Neurosci ; 32(6): 2166-81, 2012 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-22323729

RESUMEN

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.


Asunto(s)
Potenciales de Acción/fisiología , Calcio/fisiología , AMP Cíclico/fisiología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/fisiología , Neuronas Dopaminérgicas/fisiología , Canales de Potasio/fisiología , Animales , Animales Recién Nacidos , Canales de Calcio/fisiología , Femenino , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Masculino , Ratas , Ratas Wistar
7.
Commun Biol ; 6(1): 1146, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37950046

RESUMEN

Here we present a deep learning-based image analysis platform (DLAP), tailored to autonomously quantify cell numbers, and fluorescence signals within cellular compartments, derived from RNAscope or immunohistochemistry. We utilised DLAP to analyse subtypes of tyrosine hydroxylase (TH)-positive dopaminergic midbrain neurons in mouse and human brain-sections. These neurons modulate complex behaviour, and are differentially affected in Parkinson's and other diseases. DLAP allows the analysis of large cell numbers, and facilitates the identification of small cellular subpopulations. Using DLAP, we identified a small subpopulation of TH-positive neurons (~5%), mainly located in the very lateral Substantia nigra (SN), that was immunofluorescence-negative for the plasmalemmal dopamine transporter (DAT), with ~40% smaller cell bodies. These neurons were negative for aldehyde dehydrogenase 1A1, with a lower co-expression rate for dopamine-D2-autoreceptors, but a ~7-fold higher likelihood of calbindin-d28k co-expression (~70%). These results have important implications, as DAT is crucial for dopamine signalling, and is commonly used as a marker for dopaminergic SN neurons.


Asunto(s)
Aprendizaje Profundo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Animales , Humanos , Ratones , Dopamina , Neuronas Dopaminérgicas , Sustancia Negra
8.
J Neurosci ; 30(13): 4687-92, 2010 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-20357119

RESUMEN

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.


Asunto(s)
Memoria a Corto Plazo/fisiología , Neuronas/fisiología , Animales , Braquiuros , Ganglios de Invertebrados/fisiología , Potenciales de la Membrana , Técnicas de Placa-Clamp , Periodicidad , Sinapsis/fisiología
9.
eNeuro ; 8(4)2021.
Artículo en Inglés | MEDLINE | ID: mdl-34131060

RESUMEN

Substantia 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 (AP) and a biphasic postinhibitory response. The transient A-type current (IA) is known to play a crucial role in this electrical phenotype, and so far, this current was considered to be carried exclusively by Kv4.3 potassium channels. Using Kv4.3-/- transgenic mice, we demonstrate that the constitutive loss of this channel is associated with increased exploratory behavior and impaired motor learning at the behavioral level. Consistently, it is also associated with a lack of compensatory changes in other ion currents at the cellular level. Using antigen retrieval (AR) immunohistochemistry, we then demonstrate that Kv4.2 potassium channels are also expressed in SNc DA neurons, although their contribution to IA appears significant only in a minority of neurons (∼5-10%). Using correlative analysis on recorded electrophysiological parameters and multicompartment modeling, we then demonstrate that, rather than its conductance level, IA gating kinetics (inactivation time constant) appear as the main biophysical property defining postinhibitory 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.


Asunto(s)
Neuronas Dopaminérgicas , Sustancia Negra , Potenciales de Acción , Animales , Ratones , Ratones Transgénicos , Porción Compacta de la Sustancia Negra
10.
Cell Rep ; 37(4): 109884, 2021 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-34706225

RESUMEN

Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice. TAFA4 requires functional low-density lipoprotein receptor-related proteins (LRPs) because their inhibition by RAP (receptor-associated protein) dose-dependently abolishes its antihypersensitive actions. SNI selectively decreases A-type K+ current (IA) in spinal lamina II outer excitatory interneurons (L-IIo ExINs) and induces a concomitant increase in IA and decrease in hyperpolarization-activated current (Ih) in lamina II inner inhibitory interneurons (L-IIi InhINs). Remarkably, SNI-induced ion current alterations in both IN subtypes were rescued by TAFA4 in an LRP-dependent manner. We provide insights into the mechanism by which TAFA4 reverses injury-induced mechanical hypersensitivity by restoring normal spinal neuron activity and highlight the considerable potential of TAFA4 as a treatment for injury-induced mechanical pain.


Asunto(s)
Citocinas/metabolismo , Hiperalgesia/metabolismo , Dolor/metabolismo , Potasio/metabolismo , Receptores de LDL/metabolismo , Asta Dorsal de la Médula Espinal/metabolismo , Animales , Células CHO , Cricetulus , Células HEK293 , Humanos , Ratones , Células RAW 264.7
11.
J Neurosci ; 29(17): 5573-86, 2009 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-19403824

RESUMEN

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.


Asunto(s)
Conducción Nerviosa/fisiología , Redes Neurales de la Computación , Animales , Crustáceos , Fenómenos Electrofisiológicos/fisiología , Neuronas/citología , Neuronas/fisiología , Potenciales Sinápticos/fisiología
12.
Nat Neurosci ; 9(3): 356-62, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16444270

RESUMEN

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.


Asunto(s)
Braquiuros/fisiología , Ganglios de Invertebrados/metabolismo , Sistema Nervioso/metabolismo , Neuronas/metabolismo , Canales de Potasio Shal/metabolismo , Potenciales de Acción/genética , Animales , Relojes Biológicos/genética , Braquiuros/citología , Comunicación Celular/genética , Ganglios de Invertebrados/citología , Uniones Comunicantes/genética , Regulación de la Expresión Génica/fisiología , Potenciales de la Membrana/genética , Datos de Secuencia Molecular , Sistema Nervioso/citología , Conducción Nerviosa/genética , Inhibición Neural/genética , Neuronas/citología , Técnicas de Placa-Clamp , Potasio/metabolismo , ARN Mensajero/metabolismo , Canales de Potasio Shal/genética
13.
Front Cell Neurosci ; 13: 570, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-32038171

RESUMEN

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.

14.
Sci Rep ; 8(1): 13637, 2018 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-30206240

RESUMEN

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.


Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Regulación de la Expresión Génica/genética , Canales Iónicos/genética , Neurotransmisores/genética , Animales , Dopamina/genética , Dopamina/metabolismo , Fenómenos Electrofisiológicos , Canales Iónicos/metabolismo , Mesencéfalo/metabolismo , Ratones , Ratones Transgénicos , Neurotransmisores/metabolismo , Sustancia Negra/metabolismo , Área Tegmental Ventral/metabolismo
15.
J Neurosci ; 24(32): 7063-73, 2004 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-15306640

RESUMEN

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.


Asunto(s)
Axones/efectos de los fármacos , Ganglios de Invertebrados/efectos de los fármacos , Neuronas/efectos de los fármacos , Octopamina/farmacología , Potenciales de Acción , Animales , Axones/fisiología , Braquiuros , Sistema Digestivo/inervación , Vías Eferentes/citología , Vías Eferentes/fisiología , Vías Eferentes/ultraestructura , Ganglios de Invertebrados/fisiología , Ganglios de Invertebrados/ultraestructura , Fenómenos Fisiológicos del Sistema Nervioso/efectos de los fármacos , Neuronas/fisiología , Neuronas/ultraestructura , Octopamina/fisiología , Periodicidad
16.
J Neurosci ; 22(3): 886-900, 2002 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-11826118

RESUMEN

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.


Asunto(s)
Terminales Presinápticos/metabolismo , Receptores de Serotonina/metabolismo , Corteza Somatosensorial/fisiología , Transmisión Sináptica/fisiología , Tálamo/fisiología , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Técnicas In Vitro , Ratones , Ratones Endogámicos , Ratones Noqueados , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Terminales Presinápticos/efectos de los fármacos , Piridinas/farmacología , Pirroles/farmacología , ARN Mensajero/metabolismo , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/deficiencia , Receptores de Serotonina/genética , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Corteza Somatosensorial/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/crecimiento & desarrollo , Núcleos Talámicos Ventrales/crecimiento & desarrollo , Núcleos Talámicos Ventrales/metabolismo
18.
Elife ; 3: e02615, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24692452

RESUMEN

Drugs could treat neuropathic pain more effectively if they simultaneously targeted two or more types of ion channel.


Asunto(s)
Ganglios Espinales/lesiones , Ganglios Espinales/fisiopatología , Neuralgia/fisiopatología , Animales , Masculino
19.
Elife ; 32014 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-25329344

RESUMEN

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.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Fenómenos Electrofisiológicos , Dinámicas no Lineales , Porción Compacta de la Sustancia Negra/crecimiento & desarrollo , Porción Compacta de la Sustancia Negra/fisiología , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Membrana Celular/fisiología , Análisis por Conglomerados , Femenino , Masculino , Análisis Multivariante , Inhibición Neural/fisiología , Fenotipo , Análisis de Componente Principal , Ratas Wistar , Reproducibilidad de los Resultados
20.
PLoS One ; 9(9): e106803, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25265278

RESUMEN

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.


Asunto(s)
Señalización del Calcio , Factor de Crecimiento Epidérmico/metabolismo , Animales , Células COS , Calcio/metabolismo , Chlorocebus aethiops , Receptores ErbB/metabolismo , Humanos , Cinética
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