Long-term potentiation depends on release of d-serine from astrocytes

Abstract

The role of astrocytes in synaptic plasticity has remained controversial. It has been suggested that astrocytes, the star-shaped glial cells found in the brain and spinal cord that were once considered merely passive support cells, are involved in inducing LTP (long-term potentiation) of synaptic transmission — a model for the mechanisms of memory — via the modulation of NMDA-receptor activation and postsynaptic Ca2+ entry. A new study provides more support for that theory by demonstrating that the inhibition of d-serine release from individual astrocytes blocks the potentiation of many nearby neuronal junctions. The involvement of astroglia in long-term potentiation (LTP) of synaptic transmission remains controversial. Clamping internal Ca2+ in individual astrocytes in the CA1 area of the hippocampus is now shown to block LTP induction at nearby excitatory synapses through an effect on the N-methyl-D-aspartate receptor. This LTP blockade can be reversed by exogenous D-serine, normally released in a Ca2+-dependent manner from astrocytes. Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory1. The classical form of LTP relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist d-serine2,3,4. Release of d-serine from glia enables LTP in cultures5 and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus4. However, increases in Ca2+ concentration in astroglia can also release other signalling molecules, most prominently glutamate6,7,8, ATP9 and tumour necrosis factor-α10,11, whereas neurons themselves can synthesize and supply d-serine12,13. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA1 (refs 14–16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned17,18. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous d-serine or glycine, whereas depletion of d-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca2+-dependent release of d-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.