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Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic [Ca.sup.2+] concentration ([[Ca.sup.2+]].) in pericytes activated chloride efflux through the [Ca.sup.2+]-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [[[Ca.sup.2+]].sub.i] rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [[[Ca.sup.2+]].sub.i] rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer's disease and vascular dementia., Introduction Cerebral blood flow (CBF) is regulated both at the arteriole and at the capillary level (1, 2). Capillaries are the site of the highest vascular resistance within the brain [...]

In microglia, changes in intracellular calcium concentration ([Ca2+]i) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca2+ activity, microglial Ca2+ signals are much rarer and poorly understood. Here, we studied [Ca2+]i changes of microglia in acute brain slices using Fluo-4–loaded cells and mice expressing GCaMP5g in microglia. Spontaneous Ca2+ transients occurred ~ 5 times more frequently in individual microglial processes than in their somata. We assessed whether microglial Ca2+ responses change in Alzheimer's disease (AD) using AppNL−G−F knock-in mice. Proximity to Aβ plaques strongly affected microglial Ca2+ activity. Although spontaneous Ca2+ transients were unaffected in microglial processes, they were fivefold more frequent in microglial somata near Aβ plaques than in wild-type microglia. Microglia away from Aβ plaques in AD mice showed intermediate properties for morphology and Ca2+ responses, partly resembling those of wild-type microglia. By contrast, somatic Ca2+ responses evoked by tissue damage were less intense in microglia near Aβ plaques than in wild-type microglia, suggesting different mechanisms underlying spontaneous vs. damage-evoked Ca2+ signals. Finally, as similar processes occur in neurodegeneration and old age, we studied whether ageing affected microglial [Ca2+]i. Somatic damage-evoked Ca2+ responses were greatly reduced in microglia from old mice, as in the AD mice. In contrast to AD, however, old age did not alter the occurrence of spontaneous Ca2+ signals in microglial somata but reduced the rate of events in processes. Thus, we demonstrate distinct compartmentalised Ca2+ activity in microglia from healthy, aged and AD-like brains. [ABSTRACT FROM AUTHOR]

Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles. In acute brain slices, NA contracted pericytes but did not raise the pericyte cytoplasmic Ca2+ concentration, while the α1 agonist phenylephrine did not evoke contraction. Blocking α2 adrenergic receptors (α2Rs, which induce contraction by inhibiting cAMP production), greatly reduced the NA-evoked pericyte contraction, whereas stimulating α2Rs using xylazine (a sedative) or clonidine (an anti-hypertensive drug) evoked pericyte contraction. Noradrenaline-evoked pericyte contraction and capillary constriction are thus mediated via α2Rs. Consequently, α2Rs may not only modulate CBF in health and pathological conditions, but also contribute to CBF changes evoked by α2R ligands administered in research, veterinary and clinical settings. [ABSTRACT FROM AUTHOR]

Ischaemia damages nerve myelin by depriving neurons and their myelinating oligodendrocytes of oxygen and glucose; here it is shown that ischaemic damage is caused through the H.sup.+-dependent activation of TRPA1 channels, and not via glutamate receptors of the NMDA type, as previously thought, providing a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. TRP channels damaged in ischaemia Fast nerve conduction relies on the insulating sheaths of myelin produced by glial cells -- oligodendrocytes -- of the white matter. These cells can be damaged by deprivation of blood oxygen (ischaemia) during stroke and other circulatory disturbances. David Attwell and colleagues show that ischaemic damage to oligodendrocytes causes elevation of intracellular Ca.sup.2+ levels through H.sup.+-dependent activation of TRPA1 receptors, and not via glutamate receptors of the NMDA type, as previously thought. The results provide a new mechanism and promising therapeutic targets for diseases as diverse and prevalent as cerebral palsy, spinal cord injury, stroke and multiple sclerosis. The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca.sup.2+-dependent manner, abolishing action potential propagation.sup.1,2. This has been attributed to glutamate release activating Ca.sup.2+-permeable N-methyl-d-aspartate (NMDA) receptors.sup.2,3,4. Surprisingly, we now show that NMDA does not raise the intracellular Ca.sup.2+ concentration ([Ca.sup.2+].sub.i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current.sup.4, this is generated by a rise of extracellular [K.sup.+] and decrease of membrane K.sup.+ conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca.sup.2+].sub.i, [Mg.sup.2+].sub.i and [H.sup.+].sub.i, and buffering intracellular pH reduces the [Ca.sup.2+].sub.i and [Mg.sup.2+].sub.i increases, showing that these are evoked by the rise of [H.sup.+].sub.i. The H.sup.+-gated [Ca.sup.2+].sub.i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia., Author(s): Nicola B. Hamilton [sup.1] , Karolina Kolodziejczyk [sup.1] [sup.2] , Eleni Kougioumtzidou [sup.1] , David Attwell [sup.1] Author Affiliations: (1) Department of Neuroscience, Physiology & Pharmacology, University College London, [...]