Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B

<p>Abstract</p> <p>Background</p> <p>The axon initial segment (AIS) plays a crucial role: it is the site where neurons initiate their electrical outputs. Its composition in terms of voltage-gated sodium (Nav) and voltage-gated potassium (Kv) channels, as well as its length and localization determine the neuron's spiking properties. Some neurons are able to modulate their AIS length or distance from the soma in order to adapt their excitability properties to their activity level. It is therefore crucial to characterize all these parameters and determine where the myelin sheath begins in order to assess a neuron's excitability properties and ability to display such plasticity mechanisms. If the myelin sheath starts immediately after the AIS, another question then arises as to how would the axon be organized at its first myelin attachment site; since AISs are different from nodes of Ranvier, would this particular axonal region resemble a hemi-node of Ranvier?</p> <p>Results</p> <p>We have characterized the AIS of mouse somatic motor neurons. In addition to constant determinants of excitability properties, we found heterogeneities, in terms of AIS localization and Nav composition. We also identified in all α motor neurons a hemi-node-type organization, with a contactin-associated protein (Caspr)⁺paranode-type, as well as a Caspr2⁺and Kv1⁺juxtaparanode-type compartment, referred to as a para-AIS and a juxtapara (JXP)-AIS, adjacent to the AIS, where the myelin sheath begins. We found that Kv1 channels appear in the AIS, para-AIS and JXP-AIS concomitantly with myelination and are progressively excluded from the para-AIS. Their expression in the AIS and JXP-AIS is independent from transient axonal glycoprotein-1 (TAG-1)/Caspr2, in contrast to juxtaparanodes, and independent from PSD-93. Data from mice lacking the cytoskeletal linker protein 4.1B show that this protein is necessary to form the Caspr⁺para-AIS barrier, ensuring the compartmentalization of Kv1 channels and the segregation of the AIS, para-AIS and JXP-AIS.</p> <p>Conclusions</p> <p>α Motor neurons have heterogeneous AISs, which underlie different spiking properties. However, they all have a para-AIS and a JXP-AIS contiguous to their AIS, where the myelin sheath begins, which might limit some AIS plasticity. Protein 4.1B plays a key role in ensuring the proper molecular compartmentalization of this hemi-node-type region.</p

Soil and Pest Management in French Polynesian Farming Systems and Drivers and Barriers for Implementation of Practices Based on Agroecological Principles

publishedVersio

Intermediate-term results after en bloc double-lung transplantation with bronchial arterial revascularization

AbstractObjective: Between May 1990 and January 1994, 18 patients underwent en bloc double-lung transplantation with tracheal anastomosis and bronchial arterial revascularization. Because at that time it was already suggested that chronic ischemia could be a contributing factor in occurrence of obliterative bronchiolitis, the purpose of this study was to evaluate, with a follow-up ranging from 22 to 69 months, the midterm effects of bronchial arterial revascularization on development of obliterative bronchiolitis. Results: Results were assessed according to tracheal healing, functional results, rejection, infection, and incidence of obliterative bronchiolitis. There were no intraoperative deaths or reexplorations for bleeding related to bronchial arterial revascularization, but there were three hospital deaths and five late deaths, two of them related to obliterative bronchiolitis. According to the criteria previously defined, tracheal healing was assessed as grade I, IIa, or IIb in 17 patients and grade IIIa in only one patient. Early angiography (postoperative days 20 to 40) demonstrated a patent graft in 11 of the 14 patients in whom follow-up information was obtained. Ten patients are currently alive with a 43-month mean follow-up. Among the 15 patients surviving more than 1 year, functional results have been excellent except in five in whom obliterative bronchiolitis has developed and who had an early or late graft thrombosis. Furthermore, those patients had a significantly higher incidence of late acute rejection (p < 0.02), cytomegalovirus disease (p < 0.006), and bronchitis episodes (p < 0.0008) than patients free from obliterative bronchiolitis. Conclusion: We conclude that besides its immediate beneficial effect on tracheal healing, long-lasting revascularization was, at least in this small series, associated with an absence of obliterative bronchiolitis, thus suggesting but not yet proving the possible role of chronic ischemia in this multifactorial disease. (J THORAC CARDIOVASC SURG 1996;112:1292-300

The Reality of Neandertal Symbolic Behavior at the Grotte du Renne, Arcy-sur-Cure, France

The question of whether symbolically mediated behavior is exclusive to modern humans or shared with anatomically archaic populations such as the Neandertals is hotly debated. At the Grotte du Renne, Arcy-sur-Cure, France, the Châtelperronian levels contain Neandertal remains and large numbers of personal ornaments, decorated bone tools and colorants, but it has been suggested that this association reflects intrusion of the symbolic artifacts from the overlying Protoaurignacian and/or of the Neandertal remains from the underlying Mousterian

In vivo assembly of the axon initial segment in motor neurons

International audienceThe axon initial segment (AIS) is responsible for both the modulation of action potentials and the maintenance of neuronal polarity. Yet, the molecular mechanisms controlling its assembly are incompletely understood. Our study in single electroporated motor neurons in mouse embryos revealed that AnkyrinG (AnkG), the AIS master organizer, is undetectable in bipolar migrating motor neurons, but is already expressed at the beginning of axonogenesis at E9.5 and initially distributed homogeneously along the entire growing axon. Then, from E11.5, a stage when AnkG is already apposed to the membrane, as observed by electron microscopy, the protein progressively becomes restricted to the proximal axon. Analysis on the global motor neurons population indicated that Neurofascin follows an identical spatio-temporal distribution, whereas sodium channels and beta 4-spectrin only appear along AnkG(+) segments at E11.5. Early patch-clamp recordings of individual motor neurons indicated that at E12.5 these nascent AISs are already able to generate spikes. Using knock-out mice, we demonstrated that neither beta 4-spectrin nor Neurofascin control the distal-to-proximal restriction of AnkG

Mise en évidence de nouveaux partenaires régulateurs du canal sodium potentiel-dépendant neuronal

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Etude des protéines associées au canal sodium potentiel-dépendant neuronal

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging

Antibodies normally do not cross the blood-brain barrier (BBB) and cannot bind an intracellular cerebral antigen. We demonstrate here for the first time that a new class of antibodies can cross the BBB without treatment. Camelids produce native homodimeric heavy-chain antibodies, the paratope being composed of a single-variable domain called VHH. Here, we used recombinant VHH directed against human glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. Only basic VHHs (e.g., pI=9.4) were able to cross the BBB in vitro (7.8 vs. 0% for VHH with pI=7.7). By intracarotid and intravenous injections into live mice, we showed that these basic VHHs are able to cross the BBB in vivo, diffuse into the brain tissue, penetrate into astrocytes, and specifically label GFAP. To analyze their ability to be used as a specific transporter, we then expressed a recombinant fusion protein VHH-green fluorescent protein (GFP). These "fluobodies" specifically labeled GFAP on murine brain sections, and a basic variant (pI=9.3) of the fusion protein VHH-GFP was able to cross the BBB and to label astrocytes in vivo. The potential of VHHs as diagnostic or therapeutic agents in the central nervous system now deserves attention. Li, T., Bourgeois, J.-P., Celli, S., Glacial, F., Le Sourd, A.-M., Mecheri, S., Weksler, B., Romero, I., Couraud, P.-O., Rougeon, F., and Lafaye, P. Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging