Development of the cortical map is experience dependent, with different critical periods in different cortical layers. Previous
work in rodent barrel cortex indicates that sensory deprivation leads ...to changes in synaptic transmission and plasticity in
layer 2/3 and 4. Here, we studied the impact of sensory deprivation on the intrinsic properties of layer 5 pyramidal neurons
located in rat barrel cortex using simultaneous somatic and dendritic recording. Sensory deprivation was achieved by clipping
all the whiskers on one side of the snout. Loss of sensory input did not change somatic active and resting membrane properties,
and did not influence dendritic action potential (AP) backpropagation. In contrast, sensory deprivation led to an increase
in the percentage of layer 5 pyramidal neurons showing burst firing. This was associated with a reduction in the threshold
for generation of dendritic calcium spikes during high-frequency AP trains. Cell-attached recordings were used to assess changes
in the properties and expression of dendritic HCN channels. These experiments indicated that sensory deprivation caused a
decrease in HCN channel density in distal regions of the apical dendrite. To assess the contribution of HCN down-regulation
on the observed increase in dendritic excitability following sensory deprivation, we investigated the impact of blocking HCN
channels. Block of HCN channels removed differences in dendritic calcium electrogenesis between control and deprived neurons.
In conclusion, these observations indicate that sensory loss leads to increased dendritic excitability of cortical layer 5
pyramidal neurons. Furthermore, they suggest that increased dendritic calcium electrogenesis following sensory deprivation
is mediated in part via down-regulation of dendritic HCN channels.
Classically, GABAB receptors are thought to regulate neuronal excitability via G‐protein‐coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABAB receptors can ...also activate two‐pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non‐specific GIRK channel blocker barium (200 μm) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin‐Q, a specific GIRK channel blocker. Tertiapin‐Q partially blocked GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two‐pore domain potassium channels, the non‐specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB responses mediated by two‐pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABAB receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two‐pore domain potassium channel activity.
Classically, GABAB receptors are thought to activate G‐protein‐coupled inwardly rectifying potassium channels (GIRK channels). In contrast, we show here that GABAB receptors can be coupled to both GIRK and two‐pore domain potassium channels and that this coupling is both cell and pH dependent. This pH‐dependency may act to maintain constant levels of GABAB inhibition during hypoxia.
Airway remodeling is an important process in response to repetitive inflammatory‐mediated airway wall injuries. This is characterized by profound changes and reorganizations at the cellular and ...molecular levels of the lung tissue. It is of particular importance to understand the mechanisms involved in airway remodeling, as this is strongly associated with severe asthma leading to devastating airway dysfunction. In this study, we have investigated the transforming growth factor‐β (TGFβ, a proinflammatory mediator)‐activated fibroblast to myofibroblast transdifferentiation pathway, which plays a key role in asthma‐related airway remodeling. We show that TGFβ induces fibroblast to myofibroblast transdifferentiation by the expression of αSMA, a specific myofibroblast marker. Furthermore, Smad2/Smad3 gene and protein expression patterns are different between fibroblasts and myofibroblasts. Such a change in expression patterns reveals an important role of these proteins in the cellular phenotype as well as their regulation by TGFβ during cellular transdifferentiation. Interestingly, our data show a myofibroblastic TGFβ‐mediated increase in glucocorticoid receptor (GR) expression and a preferential localization of GR in the nucleus, compared to in fibroblasts. Furthermore, the GRβ (nonfunctional GR isoform) is increased relative to GRα (functional isoform) in myofibroblasts. These results are interesting as they support the idea of a GRβ‐mediated glucocorticoid resistance observed in the severe asthmatic population. All together, we provide evidence that key players are involved in the TGFβ‐mediated fibroblast to myofibroblast transdifferentiation pathway in a human lung fibroblast cell line. These players could be the targets of new treatments to limit airway remodeling and reverse glucocorticoid resistance in severe asthma.
Myofibroblasts have an important role in airway remodeling. We show a myofibroblastic transforming growth factor‐β (TGFβ)‐mediated increase in glucocorticoid receptor (GR) expression and a preferential localization of GR in the nucleus, compared to fibroblasts. Furthermore, the GRβ subunit (nonfunctional isoform) is increased relative to GRα (functional isoform) in myofibroblasts. These results support the idea of GRβ mediated glucocorticoid resistance as observed in severe asthmatic remodeled airways.
Background:
Recent evidence suggests that oxytocin (OT), secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN) neurons, produces ...antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception.
Results:
We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II). This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages.
Conclusion:
Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.
As for all the Caribbean territories, the departments of Guadeloupe and Martinique, which were once marked by very high population growth rates, have experienced a decrease in population growth and ...even a decline in recent years. Emigration, more than fertility decline, is the main cause of this phenomenon. More than the number of individuals leaving these territories, the problem is that of their profile: the most qualified have left the territory generally in a long-term perspective. This phenomenon is particularly worrying in territories with an unprecedented rythm of ageing in France. The challenge for these two departments will be to use this ageing as an opportunity.
Inhibitory synaptic transmission in the dorsal horn (DH) of the spinal cord plays an important role in the modulation of nociceptive messages because pharmacological blockade of spinal GABAA ...receptors leads to thermal and mechanical pain symptoms. Here, we show that during the development of thermal hyperalgesia and mechanical allodynia associated with inflammatory pain, synaptic inhibition mediated by GABAA receptors in lamina II of the DH was in fact markedly increased. This phenomenon was accompanied by an upregulation of the endogenous production of 5alpha-reduced neurosteroids, which, at the spinal level, led to a prolongation of GABAA receptor-mediated synaptic currents and to the appearance of a mixed GABA/glycine cotransmission. This increased inhibition was correlated with a selective limitation of the inflammation-induced thermal hyperalgesia, whereas mechanical allodynia remained unaffected. Our results show that peripheral inflammation activates an endogenous neurosteroid-based antinociceptive control, which discriminates between thermal and mechanical hyperalgesia.
Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic ...conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of lambda -carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABAA receptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.
Classically, GABA
receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABA
receptors can ...also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABA
receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μm) abolished outward currents evoked by GABA
receptors in CA1 pyramidal, but only partially blocked GABA
responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABA
responses in CA1 pyramidal neurons, but was ineffective in blocking GABA
responses in neocortical layer 5 neurons. Consistent with the idea that GABA
receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABA
responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABA
responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABA
receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABA
inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.
Background
Growing evidence in the literature shows that oxytocin (OT) has a strong spinal anti-nociceptive action. Oxytocinergic axons originating from a subpopulation of paraventricular ...hypothalamic neurons establish synaptic contacts with lamina II interneurons but little is known about the functional role of OT with respect to neuronal firing and excitability.
Results
Using the patch-clamp technique, we have recorded lamina II interneurons in acute transverse lumbar spinal cord slices of rats (15 to 30 days old) and analyzed the OT effects on action potential firing ability. In the current clamp mode, we found that bath application of a selective OT-receptor agonist (TGOT) reduced firing in the majority of lamina II interneurons exhibiting a bursting firing profile, but never in those exhibiting a single spike discharge upon depolarization. Interestingly, OT-induced reduction in spike frequency and increase of firing threshold were often observed, leading to a conversion of the firing profile from repetitive and delayed profiles into phasic ones and sometimes further into single spike profile. The observed effects following OT-receptor activation were completely abolished when the OT-receptor agonist was co-applied with a selective OT-receptor antagonist. In current and voltage clamp modes, we show that these changes in firing are strongly controlled by voltage-gated potassium currents. More precisely, transient IA currents and delayed-rectifier currents were reduced in amplitude and transient IA current was predominantly inactivated after OT bath application.
Conclusion
This effect of OT on the firing profile of lamina II neurons is in good agreement with the antinociceptive and analgesic properties of OT described in vivo.
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