ASTROCYTIC CONTRIBUTION TO ACTIVITY-DEPENDENT GLYCINE RELEASE

In the hippocampus, high frequency stimulation (HFS) of the Schaffer collaterals causes a transient increase in extracellular glycine in CA1 stratum radiatum (Zhang et al, 2018). However, the underlying molecular mechanisms, cellular origin and physiological relevance of this activity-dependent glycine release remain elusive. We used a FRET-based glycine sensor in acute hippocampal slices to investigate this phenomenon. First, we explored the molecular mechanisms behind activity-dependent glycine release. We found that postsynaptic receptor activity is necessary, and local depolarization sufficient, to increase extracellular glycine. Moreover, glutamate transporters (EAATs) are also required for activity-dependent glycine release. Given that EAAT-mediated glutamate uptake leads to depolarization and intracellular Na+ increase, it might facilitate glycine transporter 1 (GlyT1) activity reversal (glycine export). Indeed, inhibition of GlyT1 increased basal glycine levels and prevented the glycine increase caused by HFS. Next, to confirm the cellular origin of this glycine release, we employed an astrocyte-specific GlyT1 conditional knockout mouse model. Astrocytic deletion of GlyT1 abolished glycine release during HFS. Finally, to explore the physiological relevance of activity-dependent glycine release, we tested the effect of astrocytic GlyT1 deletion on LTP induction. Surprisingly, astrocytic GlyT1 knockout animals showed an increase in LTP magnitude and blocking GlyRs in slices from control mice mimics this effect. Taken together, our results show that, during HFS, astrocytes release glycine via GlyT1; which is driven by local depolarization and glutamate uptake. Moreover, astrocytic GlyT1 regulates the magnitude of LTP in the ventral hippocampus and may play a role in learning and memory mechanisms.