Regulation of Axonal HCN1 Trafficking in Perforant Path Involves Expression of Specific TRIP8b Isoforms

The functions of HCN channels in neurons depend critically on their subcellular localization, requiring fine-tuned machinery that regulates subcellular channel trafficking. Here we provide evidence that regulatory mechanisms governing axonal HCN channel trafficking involve association of the channels with specific isoforms of the auxiliary subunit TRIP8b. In the medial perforant path, which normally contains HCN1 channels in axon terminals in immature but not in adult rodents, we found axonal HCN1 significantly increased in adult mice lacking TRIP8b (TRIP8b−/−). Interestingly, adult mice harboring a mutation that results in expression of only the two most abundant TRIP8b isoforms (TRIP8b[1b/2]−/−) exhibited an HCN1 expression pattern similar to wildtype mice, suggesting that presence of one or both of these isoforms (TRIP8b(1a), TRIP8b(1a-4)) prevents HCN1 from being transported to medial perforant path axons in adult mice. Concordantly, expression analyses demonstrated a strong increase of expression of both TRIP8b isoforms in rat entorhinal cortex with age. However, when overexpressed in cultured entorhinal neurons of rats, TRIP8b(1a), but not TRIP8b(1a-4), altered substantially the subcellular distribution of HCN1 by promoting somatodendritic and reducing axonal expression of the channels. Taken together, we conclude that TRIP8b isoforms are important regulators of HCN1 trafficking in entorhinal neurons and that the alternatively-spliced isoform TRIP8b(1a) could be responsible for the age-dependent redistribution of HCN channels out of perforant path axon terminals

Correlation between magnetic resonance, X-ray imaging alterations and histological changes in an ovine model of age-related disc degeneration

International audienceSheep are one of the many animal models used to investigate the pathophysiology of disc degeneration and the regenerative strategies for intervertebral disc (IVD) disease. To date, few studies have thoroughly explored ageing of ovine lumbar IVDs. Hence, the objective of the present study was to concomitantly assess the development of spontaneous age-related lumbar IVD degeneration in sheep using X-ray, magnetic resonance imaging (MRI) as well as histological analyses. 8 young ewes ( 48 months old) were included. Disc height, Pfirrmann and modified Pfirrmann grades as well as T2-wsi and T2 times were assessed by X-ray and MRI. The modified Boos score was also determined using histology sections. Pfirrmann (2 to 3) and modified Pfirrmann (2 to 4) grades as well as Boos scores (7 to 13) gradually increased with ageing, while T2-weighted signal intensity (1.18 to 0.75), T2 relaxation time (114.36 to 70.65 ms) and disc height (4.1 to 3.2 mm) decreased significantly. All the imaging modalities strongly correlated with the histology (p < 0.0001). The present study described the suitability of sheep as a model of age-related IVD degeneration by correlation of histological tissue alterations with the changes observed using X-ray and MRI. Given the structural similarities with humans, the study demonstrated that sheep warrant being considered as a pertinent animal model to investigate IVD regenerative strategies without induction of degeneration

Alterations in Wall Shear Stress Predict Sites of Neointimal Hyperplasia after Stent Implantation in Rabbit Iliac Arteries

Restenosis resulting from neointimal hyperplasia (NH) limits the effectiveness of intravascular stents. Rates of restenosis vary with stent geometry, but whether stents affect spatial and temporal distributions of wall shear stress (WSS) in vivo is unknown. We tested the hypothesis that alterations in spatial WSS after stent implantation predict sites of NH in rabbit iliac arteries. Antegrade iliac artery stent implantation was performed under angiography, and blood flow was measured before casting 14 or 21 days after implantation. Iliac artery blood flow domains were obtained from three-dimensional microfocal X-ray computed tomography imaging and reconstruction of the arterial casts. Indexes of WSS were determined using three-dimensional computational fluid dynamics. Vascular histology was unchanged proximal and distal to the stent. Time-dependent NH was localized within the stented region and was greatest in regions exposed to low WSS and acute elevations in spatial WSS gradients. The lowest values of WSS spatially localized to the stented area of a theoretical artery progressively increased after 14 and 21 days as NH occurred within these regions. This NH abolished spatial disparity in distributions of WSS. The results suggest that stents may introduce spatial alterations in WSS that modulate NH in vivo

T-cell and Transcriptomic Responses to Prime-boost Strategies of 3 HIV Vaccines(MVA HIV-B; LIPO-5; GTU-MultiHIV B)-ANRS/INSERM VRI01 Trial

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