title: In vivo D-serine hetero-exchange through alanine-serine-cysteine (ASC) transporters detected by microelectrode biosensors.
abstract: D-serine, a co-agonist of N-methyl D-aspartate (NMDA) receptors, has been implicated in neurological and psychiatric disorders such as cerebral ischemia, lateral amyotrophic sclerosis, or schizophrenia. D-serine signaling represents an important pharmacological target for treating these diseases; however, the biochemical mechanisms controlling extracellular D-serine levels in vivo are still unclear. D-serine heteroexchange through small neutral amino acid transporters has been shown in cell cultures and brain slices and could provide a biochemical mechanism for the control of D-serine extracellular concentration in vivo. Alternatively, exocytotic D-serine release has also been proposed. In this study, the dynamics of D-serine release and clearance were explored in vivo on a second-by-second time scale using microelectrode biosensors. The rate of D-serine clearance in the rat frontal cortex after a microionophoretic injection revealed a transporter-mediated uptake mechanism. D-serine uptake was blocked by small neutral l-amino acids, implicating alanine-serine-cysteine (ASC) transporters, in particular high affinity Asc-1 and low affinity ASCT2 transporters. Interestingly, changes in alanine, serine, or threonine levels resulted in D-serine release through ASC transporters. Asc-1, but not ASCT2, appeared to release D-serine in response to changes in amino acid concentrations. Finally, neuronal silencing by tetrodotoxin increased D-serine extracellular concentration by an ASC-transporter-dependent mechanism. Together, these results indicate that D-serine heteroexchange through ASC transporters is present in vivo and may constitute a key component in the regulation of D-serine extracellular concentration.
authors.affiliation: INSERM U1028; CNRS UMR5292 Lyon Neuroscience Research Center, AniRA-Neurochem technological platform, team WAKING, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Maucler
authors.forename: Pierre
authors.initials: P
authors.lastname: Pernot
authors.forename: Natalia
authors.initials: N
authors.lastname: Vasylieva
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marinesco
mesh_terms: D026962:Amino Acid Transport System ASC / Q000502:physiology*; D000818:Animals; D015374:Biosensing Techniques; D005625:Frontal Lobe / Q000378:metabolism*; D008839:Microelectrodes; D015778:Minor Histocompatibility Antigens; D051381:Rats; D012694:Serine / Q000378:metabolism*
chemical_list: D026962:Amino Acid Transport System ASC; D015778:Minor Histocompatibility Antigens; C498849:Slc1a5 protein, rat; C583864:Slc7a10 protein, rat; D012694:Serine