Astrocytic control of synaptic NMDA receptors

Abstract

Astrocytes express a wide range of G-protein coupled receptors that trigger release of intracellular Ca 2+ , including P2Y, bradykinin and protease activated receptors (PARs). By using the highly sensitive sniffer-patch technique, we demonstrate that the activation of P2Y receptors, bradykinin receptors and protease activated receptors all stimulate glutamate release from cultured or acutely dissociated astrocytes. Of these receptors, we have utilized PAR1 as a model system because of favourable pharmacological and molecular tools, its prominent expression in astrocytes and its high relevance to neuropathological processes. Astrocytic PAR1-mediated glutamate release in vitro is Ca 2+ dependent and activates NMDA receptors on adjacent neurones in culture. Activation of astrocytic PAR1 in hippocampal slices induces an APV-sensitive inward current in CA1 neurones and causes APV-sensitive neuronal depolarization in CA1 neurones, consistent with release of glutamate from astrocytes. PAR1 activation enhances the NMDA receptor-mediated component of synaptic miniature EPSCs, evoked EPSCs and evoked EPSPs in a Mg 2+ -dependent manner, which may reflect spine head depolarization and consequent reduction of NMDA receptor Mg 2+ block during subsequent synaptic currents. The release of glutamate from astrocytes following PAR1 activation may also lead to glutamate occupancy of some perisynaptic NMDA receptors, which pass current following relief of tonic Mg 2+ block during synaptic depolarization. These results suggest that astrocytic G-protein coupled receptors that increase intracellular Ca 2+ can tune synaptic NMDA receptor responses.

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

“…In the CNS, PAR‐1 is expressed mainly (and in some areas almost exclusively) by astrocytes although in the hippocampus PAR‐1 is also present in some neurons (Junge et al, 2004; Niclou, Suidan, Brown‐Luedi, & Monard, 1994; Wang, Ubl, & Reiser, 2002). Activation of PAR‐1 leads to increases in astrocytic [Ca 2+ ] i and astrocytes activated by PAR‐1 agonists can release glutamate which, in turn, may activate NMDA receptors on adjacent neurons (Lee et al, 2007; Vance, Rogers, & Hermann, 2015). …”

A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes

“…The virus-infected mouse brain slices (350 mm) containing hippocampus were acutely prepared using a vibrating blade microtome (Leica VT1000 S) 55 . Prepared slices were left to recover for at least 1 h before recording in oxygenated (95% O 2 and 5% CO 2 ) artificial cerebrospinal fluid (ACSF; in mM, 130 NaCl, 24 NaHCO 3 , 3.5 KCl, 1.25 NaH 2 PO 4 , 1 CaCl 2 , 3 MgCl 2 and 10 glucose, pH 7.4; at room temperature).…”

“…Primary cortical astrocytes were prepared from 1-3-day-old male and female C57BL/6 mouse pubs 55 . The cerebral cortex was dissected free of adherent meninges, minced and dissociated into a single-cell suspension by trituration.…”

Calcium Triggers Exocytosis from Two Types of Organelles in a Single Astrocyte

“…AsRed2 (Clontech), alone as a control, or with plasmid of glutamate receptor (GluR)-L497Y (Stern-Bach et al, 1998;Lee et al, 2007), was transfected into HEK293 cells. GluR-L497Y was a gift from Dr. Stephen F. Traynelis (Department of Pharmacology, Emory University School of Medicine, Atlanta, GA).…”