Vesicular glutamate release from central axons contributes to myelin damage

Neuronal activity can lead to vesicular release of glutamate. Here the authors demonstrate that vesicular release of glutamate occurs in axons during ischemic conditions, and that an allosteric modulator of GluN2C/D is protective in models of ischemic injury

Hyperacute Detection of Neurofilament Heavy Chain in Serum Following Stroke: A Transient Sign

Serological biomarkers which enable quick and reliable diagnosis or measurement of the extent of irreversible brain injury early in the course of stroke are eagerly awaited. Neurofilaments (Nf) are a group of proteins integrated into the scaffolding of the neuronal and axonal cytoskeleton and an established biomarker of neuro-axonal damage. The Nf heavy chain (NfH(SMI35)) was assessed together with brain-specific astroglial proteins GFAP and S100B in hyperacute stroke (6 and 24 h from symptom onset) and daily for up to 6 days. Twenty-two patients with suspected stroke (median NIHSS 8) were recruited in a prospective observational study. Evidence for an ischaemic or haemorrhagic lesion on neuroimaging was found in 18 (ischaemia n = 16, intracerebral haemorrhage n = 2). Serum NfH(SMI35) levels became detectable within 24 h post-stroke (P < 0.0001) and elevated levels persisted over the study course. While GFAP was not detectable during the entire course, S100B levels peaked at the end of the observation period. The data indicate that significant in vivo information on the pathophysiology of stroke may be obtained by the determination of NfH(SMI35). Further studies are required to evaluate whether NfH(SMI35) in hyperacute stroke reflects the extent of focal ischaemic injury seen on neuroimaging or is a consequence of more diffuse neuro-axonal damage

Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity

International audienc

Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin

The balance between tissue-type plasminogen activator (tPA) and one of its inhibitors, neuroserpin, has crucial roles in the central nervous system, including the control of neuronal migration, neuronal plasticity and neuronal death. In the present study, we demonstrate that the activation of the transforming growth factor-beta (TGFbeta)-related BMPR-IB (also known as BMPR1B and Alk6)- and Smad5-dependent signalling pathways controls neuroserpin transcription. Accordingly, we demonstrate for the first time that anti-Mullerian hormone (AMH), a member of the TGFbeta family, promotes the expression of neuroserpin in cultured neurons but not in astrocytes. The relevance of these findings is confirmed by the presence of both AMH and AMH type-II receptor (AMHR-II) in brain tissues, and is supported by the observation of reduced levels of neuroserpin in the brain of AMHR-II-deficient mice. Interestingly, as previously demonstrated for neuroserpin, AMH protects neurons against N-methyl-D-aspartate (NMDA)-mediated excitotoxicity both in vitro and in vivo. This study demonstrates the existence of an AMH-dependent signalling pathway in the brain leading to an overexpression of the serine-protease inhibitor, neuroserpin, and neuronal survival

Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections

Calcium (Ca2+) release through inositol 1,4,5-trisphosphate receptors (IP3Rs) regulates the function of virtually every mammalian cell. Unlike ryanodine receptors, which generate local Ca2+ events (“sparks”) that transmit signals to the juxtaposed cell membrane, a similar functional architecture has not been reported for IP3Rs. Here, we have identified spatially fixed, local Ca2+ release events (“pulsars”) in vascular endothelial membrane domains that project through the internal elastic lamina to adjacent smooth muscle membranes. Ca2+ pulsars are mediated by IP3Rs in the endothelial endoplasmic reticulum of these membrane projections. Elevation of IP3 by the endothelium-dependent vasodilator, acetylcholine, increased the frequency of Ca2+ pulsars, whereas blunting IP3 production, blocking IP3Rs, or depleting endoplasmic reticulum Ca2+ inhibited these events. The elementary properties of Ca2+ pulsars were distinct from ryanodine-receptor-mediated Ca2+ sparks in smooth muscle and from IP3-mediated Ca2+ puffs in Xenopus oocytes. The intermediate conductance, Ca2+-sensitive potassium (KCa3.1) channel also colocalized to the endothelial projections, and blockage of this channel caused an 8-mV depolarization. Inhibition of Ca2+ pulsars also depolarized to a similar extent, and blocking KCa3.1 channels was without effect in the absence of pulsars. Our results support a mechanism of IP3 signaling in which Ca2+ release is spatially restricted to transmit intercellular signals