Neuronal release of D-serine: A physiological pathway controlling extracellular D-serine concentration

Dina Rosenberg, Elena Kartvelishvily, Maria Shleper, Chanda M.C. Klinker, Michael T. Bowser, Herman Wolosker

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


D-Serine is thought to be a glia-derived transmitter that activates N-methyl D-aspartate receptors (NMDARs) in the brain. Here, we investigate the pathways for D-serine release using primary cultures, brain slices, and in vivo microdialysis. In contrast with the notion that D-serine is exclusively released from astrocytes, we found that D-serine is released by neuronal depolarization both in vitro and in vivo. Veratridine (50 μM) or depolarization by 40 mM KCl elicits a significant release of endogenous D-serine from primary neuronal cultures. Controls with astrocyte cultures indicate that glial cells are insensitive to veratridine, but release D-serine mainly by the opening of volume-regulated anion channels. In cortical slices perfused with veratridine, endogenous D-serine release is 10-fold higher than glutamate receptor-evoked release. Release of D-serine from slices does not require internal or external Ca2+, suggesting a nonvesicular release mechanism. To confirm the neuronal origin of D-serine, we selectively loaded neurons in cortical slices with D-[3H]serine or applied D-alanine, which specifically releases D-serine from neurons. Depolarization with veratridine promotes D-serine release in vivo monitored by high temporal resolution microdialysis of the striatum. Our data indicate that the neuronal pool of D-serine plays a major role in D-serine dynamics, with implications for the regulation of NMDAR transmission.

Original languageEnglish (US)
Pages (from-to)2951-2961
Number of pages11
JournalFASEB Journal
Issue number8
StatePublished - Aug 2010


  • Microdialysis
  • NMDA receptor
  • Neurotransmission
  • Serine racemase

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