Activation of β‐adrenergic receptors in rat visual cortex expands astrocytic processes and reduces extracellular space volume

Abstract

Brain extracellular space (ECS) is an interconnected channel that allows diffusion-mediated transport of signaling molecules, metabolites, and drugs. We tested the hypothesis that β-adrenergic receptor (βAR) activation impacts extracellular diffusion-mediated transport of molecules through alterations in the morphology of astrocytes. Two structural parameters of ECS - volume fraction and tortuosity - govern extracellular diffusion. Volume fraction (α) is the volume of ECS relative to the total tissue volume. Tortuosity (λ) is a measure of the hindrance that molecules experience in the ECS, compared to a free medium. The Real-Time Iontophoretic (RTI) method revealed that treatment of acutely prepared visual cortical slices of adult female rats with a βAR agonist, DL-isoproterenol (ISO), decreases α significantly, from 0.22 ± 0.03 (mean ± SD) for controls without agonist to 0.18 ± 0.03 with ISO, without altering λ (control: 1.64 ± 0.04; ISO: 1.63 ± 0.04). Electron microscopy revealed that the ISO treatment significantly increased the cytoplasmic area of astrocytic distal endings per unit area of neuropil by 54%. These findings show that norepinephrine decreases α, in part, through an increase in astrocytic volume following βAR activation. Norepinephrine is recognized to be released within the brain during the awake state and increase neurons’ signal-to-noise ratio through modulation of neurons’ biophysical properties. Our findings uncover a new mechanism for noradrenergic modulation of neuronal signals. Through astrocytic activation leading to a reduction of α, noradrenergic modulation increases extracellular concentration of neurotransmitters and neuromodulators, thereby facilitating neuronal interactions, especially during wakefulness.

Probing nano‐organization of astroglia with multi‐color super‐resolution microscopy

“…This is mainly because direct experimental probing of the nanoscopic astrocyte structures has not been technically plausible: the sponge-like astrocyte processes fill the tissue volume featuring details that are beyond the diffraction limit of light microscopy (200-300 nm, including fluorescence confocal and two-photon excitation varieties). Historically, electron microscopy (EM) has been the only tool capable of successfully resolving astroglial structure on the nanoscale, including advanced 3D reconstruction tools to deal with PAPs (Bernardinelli et al, 2014b;Lushnikova et al, 2009;Medvedev et al, 2014;Medvedev et al, 2010;Patrushev et al, 2013;Popov et al, 2004;Sherpa et al, 2016;Witcher et al, 2007;Witcher et al, 2010). However, EM has important limitations.…”

Amines, Astrocytes, and Arousal

“…A possible alternative scenario is that astrocytes alter neurotransmitter action on surrounding neurons cell-autonomously as a result of [Ca 2+ ] i changes altering the surface expression of neurotransmitter transporters (which regulate transmitter action in flies as in mammals: MacNamee et al, 2016), or perhaps of surface membrane enzymes that hydrolyze ATP, thus altering the level of neurotransmitters or adenosine reaching the surrounding neurons (Shigetomi et al, 2011;discussed in Bazargani and Attwell, 2016). Additionally, the reported increase of astrocyte volume evoked during arousal by noradrenaline activating b receptors (Sherpa et al, 2016), which may contribute to the decrease in extracellular volume seen during wake periods , may alter the concentration of neurotransmitters in the extracellular space. Estab-lishing the mechanism of this swelling, which could reflect an increased ion influx into astrocytes or a decrease of Na/K pump activity, is an important issue for the future.…”

Novel concepts in sleep regulation

“…The increased removal of the harmful protein specifically during sleep could give reasonable explanation for these findings. It can be noted that changes in extracellular volume affect also the concentration of neurotransmitters in this space, including neurotransmitters that regulate vigilance . This is yet another mechanism for global regulation of vigilance state.…”

“…Stimulation of beta‐adrenergic receptors of rat visual cortex was reported to expand the astrocytic processes and to reduce extracellular space …”