title: Neuronal release of D-serine: a physiological pathway controlling extracellular D-serine concentration.
abstract: 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 microM) 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 Ca(2+), suggesting a nonvesicular release mechanism. To confirm the neuronal origin of D-serine, we selectively loaded neurons in cortical slices with D-[(3)H]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.
authors.affiliation: Department of Biochemistry, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Rosenberg
authors.forename: Elena
authors.initials: E
authors.lastname: Kartvelishvily
authors.forename: Maria
authors.initials: M
authors.lastname: Shleper
authors.forename: Chanda M C
authors.initials: CM
authors.lastname: Klinker
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowser
authors.forename: Herman
authors.initials: H
authors.lastname: Wolosker
mesh_terms: D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001921:Brain / Q000166:cytology*; D001923:Brain Chemistry; D002478:Cells, Cultured; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018377:Neurotransmitter Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D014701:Veratridine / Q000494:pharmacology
chemical_list: D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D014701:Veratridine