Signaling at the Gliovascular Interface

Abstract

Advances in fluorescent calcium indicating dyes over the past decade have identified calcium signaling as the tool by which astrocytes communicate among themselves and with neighboring neurons. Studies of astrocyte-neuron interactions have shown that calcium signaling is a potent modulator of the strength of both excitatory and inhibitory synapses. The concept that astrocytes possess a mechanism for rapid cell communication has not been incorporated, however, into the supportive functions of astrocytes. Because many of the classical tasks of astrocytes are linked to the blood-brain barrier, we have here examined the expression of proteins required for calcium signaling in their vascular end-foot processes. The gap junction protein, Cx43, was expressed intensively around the vessels interconnecting astrocytic end-foot processes. These gap junctions permitted diffusion of Lucifer yellow, specifically along the path of glial end feet apposed to the vessel wall. The purinergic receptors, P2Y(2) and P2Y(4), were also strongly expressed at the gliovascular interface and colocalized with GFAP around larger vessels in cortex. Multiphoton imaging of freshly prepared brain slices loaded with Fluo-4/AM revealed that ATP mobilized cytosolic calcium in astrocytic end feet, whereas electrical stimulation triggered calcium waves propagating along the vessel wall. Brain endothelial cells and pericytes were physically separated from astrocytes by the basal lamina and responded only weakly to ATP. These observations identify astrocytic end-foot processes plastered at the vessel wall as a center for purinergic signaling. It is speculated that calcium signaling may play a role in astrocytic functions related to the blood-brain barrier, including blood flow regulation, metabolic trafficking, and water homeostasis.

Interaction of Mechanisms Involving Epoxyeicosatrienoic Acids, Adenosine Receptors, and Metabotropic Glutamate Receptors in Neurovascular Coupling in Rat Whisker Barrel Cortex

“…The new finding that alloxazine does not produce additional attenuation of the response, compared with AIDA alone, is consistent with the possibility of a sequential mechanism in which A 2B receptor activation promotes the Ca 2 + signaling that is initiated within astrocytes by mGluR activation. An alternative possibility that is also consistent with the data is that mGluR-induced increased Ca 2 + causes release of ATP at astrocyte end-feet (Simard et al, 2003), where ATP might be converted into adenosine and act on vascular A 2B receptors.…”

Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease

“…9G), which might be considered as the additional evidence that activated actrocytes played an active role in the observed neuroprotection. Indeed, astrocytes can produce and release vasodilatory mediators, such as prostaglandins, nitric oxide, and arachidonic acid, which controls various aspects of the blood-brain barrier, including blood flow, metabolic trafficking, and water homeostasis (Kimelberg and Nedergaard, 2010;Simard et al, 2003;Takano et al, 2006).…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…GJ are also dense at the endfeet of astrocytes where they provide a perivascular route that facilitates intercellular trafficking between neighboring endfeet (Simard, Arcuino, Takano, Liu, & Nedergaard, 2003). Connexons exist also on their own as single membrane hemichannels which connect the cell cytoplasm to the extracellular milieu (Giaume, Leybaert, Naus, & Saez, 2013).…”