Abstract
Cortical spreading depression (CSD) is a slowly propagating wave of depolarization of gray matter. This phenomenon is believed to underlie the migraine aura and similar waves of depolarization may exacerbate injury in a number of neurological disease states. CSD is characterized by massive ion dyshomeostasis, cell swelling, and multiphasic blood flow changes. Recently, it was shown that CSD is associated with a closure of the paravascular space (PVS), a proposed exit route for brain interstitial fluid and solutes, including excitatory and inflammatory substances that increase in the wake of CSD. The PVS closure was hypothesized to rely on swelling of astrocytic endfeet due to their high expression of aquaporin‐4 (AQP4) water channels. We investigated whether CSD is associated with swelling of endfeet around penetrating arterioles in the cortex of living mice. Endfoot cross‐sectional area was assessed by two‐photon microscopy of mice expressing enhanced green fluorescent protein in astrocytes and related to the degree of arteriolar constriction. In anesthetized mice CSD triggered pronounced endfoot swelling that was short‐lasting and coincided with the initial arteriolar constriction. Mice lacking AQP4 displayed volume changes of similar magnitude. CSD‐induced endfoot swelling and arteriolar constriction also occurred in awake mice, albeit with faster kinetics than in anesthetized mice. We conclude that swelling of astrocytic endfeet is a robust event in CSD. The early onset and magnitude of the endfoot swelling is such that it may significantly delay perivascular drainage of interstitial solutes in neurological conditions where CSD plays a pathophysiological role.
Highlights
The hallmark of cortical spreading depression (CSD), a wave of neuronal hyperactivity followed by temporary silencing, was first described over 70 years ago by Artistides Leão during seizure experiments in rabbits (Leão, 1944)
Given that astrocytic endfeet may regulate the width of paravascular spaces and the turnover and composition of interstitial fluid (ISF), we chose to investigate endfoot volume dynamics in living mice subjected to CSD
Boxed area shows a penetrating arteriole and its astrocytic endfeet displayed at higher magnification in c. (c) Example two-photon images of WT and Aqp4−/− Glt1-enhanced green fluorescent protein (eGFP) BAC transgenic mice exposed to CSD
Summary
The hallmark of cortical spreading depression (CSD), a wave of neuronal hyperactivity followed by temporary silencing, was first described over 70 years ago by Artistides Leão during seizure experiments in rabbits (Leão, 1944). It was originally proposed that interstitial waste products move by convective flow, both through the brain parenchyma and along the paravascular pathways (Iliff et al, 2012), possibly driven by arterial pulsations (Iliff et al, 2013). The width of the paravascular space, interposed between the vascular tube and the glial endfoot sheath, must be a critical determinant of brain waste removal-in acute conditions as well as in neurodegenerative diseases such as Alzheimer’s disease. Given that astrocytic endfeet may regulate the width of paravascular spaces and the turnover and composition of ISF, we chose to investigate endfoot volume dynamics in living mice subjected to CSD. To determine the role of AQP4 in endfoot volume dynamics the experiments were conducted on Aqp4−/− and Aqp4+/+ Glt1-eGFP BAC mice (Thrane et al, 2011). Since anesthetic agents affect vascular tone (Zuurbier, Emons, & Ince, 2002) and intracellular signaling cascades implicated in glial volume regulation (Thrane et al, 2012), experiments were carried out in awake, unanesthetized animals
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