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

Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory. 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-serine. Release of d-serine from glia enables LTP in cultures and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus. However, increases in Ca2+ concentration in astroglia can also release other signalling molecules, most prominently glutamate, ATP and tumour necrosis factor-α, whereas neurons themselves can synthesize and supply d-serine. 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 questioned. 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.

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