The molecular mechanism of synaptic activity‐induced astrocytic volume transient

Abstract

Key points Neuronal activity causes astrocytic volume change via K+ uptake through TREK‐1 containing two‐pore domain potassium channels The volume transient is terminated by Cl− efflux through Ca2+‐activated anion channel, BEST1 The source of Ca2+ to open BEST1 appears to be the stretch‐activated TRPA1 channel Intense neuronal activity is synaptically coupled with a physical change in astrocytes via volume transients Abstract The brain volume changes dynamically and transiently upon intense neuronal activity through a tight regulation of ion concentrations and water movement across the plasma membrane of astrocytes. We have recently demonstrated that an intense neuronal activity and subsequent astrocytic AQP4‐dependent volume transient are critical for synaptic plasticity and memory. We have also pharmacologically demonstrated a functional coupling between synaptic activity and astrocytic volume transient. However, the precise molecular mechanisms of how intense neuronal activity and astrocytic volume transient are coupled remain unclear. Here we utilized intrinsic optical signal imaging technique combined with fluorescence imaging using ion sensitive dyes and molecular probes and electrophysiology to investigate the detailed molecular mechanisms in genetically modified mice. We report that a brief synaptic activity induced by a train stimulation (20 Hz, 1 s) causes a prolonged astrocytic volume transient (80 s) via K⁺ uptake through TREK‐1 containing two‐pore domain potassium (K2P) channels, but not Kir4.1 nor NKCC1. This volume change is terminated by Cl⁻ efflux through Ca²⁺‐activated anion channel BEST1, but not volume‐regulated anion channel TTYH. The source of Ca²⁺ to open BEST1 appears to be the stretch‐activated TRPA1 channel in astrocytes, but not IP₃R2. In summary, our study identifies several important astrocytic ion channels (AQP4, TREK‐1, BEST1, TRPA1) as the key molecules leading to the neuronal activity‐dependent volume transient in astrocytes. Our findings provide unprecedented molecular and cellular mechanisms of how intense neuronal activity is synaptically coupled with a physical change in astrocytes via volume transients. This article is protected by copyright. All rights reserved