Synergy between vesicular and non-vesicular gliotransmission regulates synaptic plasticity and working memory

Abstract

Astrocytes are an active element of brain signalling, capable of release of small molecule gliotransmitters by vesicular and channel-mediated mechanisms. However, specific physiological roles of astroglial exocytosis of glutamate and D-Serine remain controversial. Our data demonstrate that cortical astrocytes can release glutamate and D-Serine by combination of SNARE-dependent exocytosis and non-vesicular mechanisms dependent on TREK-1 and Best1 channels. Astrocyte-derived glutamate and D-serine elicited complex multicomponent phasic response in neocortical pyramidal neurons, which is mediated by extra-synaptic GluN2B receptors. Impairment of either pathway of gliotransmission (in the TREK1 KO, Best-1 KO or dnSNARE mice) strongly affected the NMDAR-dependent long-term synaptic plasticity in the hippocampus and neocortex. Moreover, impairment of astroglial exocytosis in dnSNARE mice led to the deficit in the spatial working memory which was rescued by environmental enrichment. We conclude that synergism between vesicular and non-vesicular gliotransmission is crucial for astrocyte-neuron communication and astroglia-driven regulation of synaptic plasticity and memory. HighlightsO_LIAstrocytes in situ release glutamate via exocytosis and channel-mediated release. C_LIO_LIAstroglia-derived glutamate and D-Serine activate phasic NMDAR currents in neurons C_LIO_LIBoth vesicular and non-vesicular gliotransmission are required for synaptic plasticity C_LIO_LIImpaired exocytosis of gliotransmitters causes deficit in working memory C_LI