Insights into the release mechanism of astrocytic glutamate evoking in neurons NMDA receptor‐mediated slow depolarizing inward currents

Abstract

The gliotransmitter glutamate in different brain regions modulates neuronal excitability and synaptic transmission through a variety of mechanisms. Among the hallmarks of astrocytic glutamate release are the slow depolarizing inward currents (SICs) in neurons mediated by N-methyl-d-aspartate receptor activation. Different stimuli that evoke Ca elevations in astrocytes induce neuronal SICs suggesting a Ca -dependent exocytotic glutamate release mechanism of SIC generation. To gain new insights into this mechanism, we investigated the relationship between astrocytic Ca elevations and neuronal SICs in mouse hippocampal slice preparations. Here we provide evidence that SICs, occurring either spontaneously or following a hypotonic challenge, are unchanged in the virtual absence of Ca signal changes at astrocytic soma and processes, including spatially restricted Ca microdomains. SICs are also unchanged in the presence of Bafilomycin A1 that after prolonged slice incubation depletes glutamate from astrocytic vesicles. We also found that hemichannels and TREK family channels-that recent studies proposed to mediate astrocytic glutamate release - are not involved in SIC generation. SICs are reduced by the volume-sensitive anion channel antagonists diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), quinine and fluoxetine, suggesting a possible contribution of these channels in SIC generation. Direct measurements of astrocytic glutamate release further confirm that hypotonicity-evoked gliotransmission is impaired following DIDS, quinine and fluoxetine while the exocytotic release of glutamate-that is proposed to mediate synaptic transmission modulation by astrocytes-remains unaffected. In conclusion, our data provide evidence that the release of glutamate generating SICs occurs independently on exocytotic Ca -dependent glutamate release mechanism.

Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke

“…Indeed, Ca 2+ -dependent SICs in CA1 pyramidal neurons evoked by protease-activated receptor 1 (PAR-1) activation in astrocytes were normal in Swell1 mutant mice (Figure S7). These data indicate the existence of VRAC-independent glutamate-releasing and SIC-generating mechanisms (Gó mez-Gonzalo et al, 2018), which may include other channel candidates, such as bestrophin-1 and hemichannels. Besides glutamate release, the concomitant reduction of the extracellular space during cell swelling markedly increases the effective glutamate concentration, which could also contribute to SIC generation (Lauderdale et al, 2015).…”

Cytoarchitectural analysis of the neuron‐to‐glia association in the dorsal root ganglia of normal and diabetic mice

“…According to the original sandwich synapse hypothesis, stimulation in a given ‘ cis’ neuron propagates to neighboring nerve cells following the activation of the purinergic P2Y12 receptors expressed by the surrounding SGCs, which have been hypothesized to release glutamate that acts onto the NMDA receptors expressed at the membrane of the ‘ trans’ neuron (Rozanski et al ., 2013). In line with such a possibility, astrocytic glutamate was shown to evoke NMDA receptor‐mediated slow depolarizing inward currents in neurons (Gómez‐Gonzalo et al ., 2018). In DRGs, the spread of excitation driven through sandwich synapses is enhanced in a variety of pathological pain conditions (Ohara et al ., 2009; Wu et al ., 2012; Kim et al ., 2016).…”

Non-canonical glutamate signaling in a genetic model of migraine with aura

“…The following references appear in the supplemental information: Amzica, 2002, Angulo et al, 2004, Araque et al, 1998a, Araque et al, 1998b, Araque et al, 2000, Fellin et al, 2004, Gó mez-Gonzalo et al, 2018, Innocenti et al, 2000, Kang et al, 1998, Mishima and Hirase, 2010, Ni and Parpura, 2009, Perea and Araque, 2005, Perea et al, 2014, Poskanzer and Yuste, 2016, Sasaki et al, 2012.…”