PMID- 21544869 OWN - NLM STAT- MEDLINE DCOM- 20110906 LR - 20220410 IS - 1098-1136 (Electronic) IS - 0894-1491 (Print) IS - 0894-1491 (Linking) VI - 59 IP - 7 DP - 2011 Jul TI - Astrocytic activation of A1 receptors regulates the surface expression of NMDA receptors through a Src kinase dependent pathway. PG - 1084-93 LID - 10.1002/glia.21181 [doi] AB - Chemical transmitters released from astrocytes, termed gliotransmitters, modulate synaptic transmission and neuronal function. Using astrocyte-specific inducible transgenicmice (dnSNARE mice), we have demonstrated that inhibiting gliotransmission leads to reduced activation of adenosine A1 receptors (A1R) and impaired sleep homeostasis (Halassa et al. (2009) Neuron 61:213-219); Pascual et al. (2005) Science 310:113-116). Additionally, synaptic N-methyl-D-aspartate receptor (NMDAR) currents are reduced in these astrocyte-specific transgenic animals (Fellin et al. (2009) Proc Natl Acad Sci USA 106:15037-15042). Because of the importance of adenosine and NMDA receptors to sleep processes we asked whether there is a causal linkage between changes in A1R activation and synaptic NMDA receptors. We show that astrocytic dnSNARE expression leads to reduced tyrosine phosphorylation of Srckinase and NR2 subunits concomitant with the decreased surface expression of the NR2 subunits. To test the role of A1R signaling in mediating these actions, we show that incubation of wildtype (WT) slices with an A1R antagonist reduces tyrosine phosphorylation of Src kinase and NR2B, decreases the surface expression of the NR2B subunits and leads to smaller NMDA component of miniature EPSCs. In dnSNARE mice we could rescue WT phenotype by incubation in an A1R agonist:activation of A1 receptor led to increased tyrosine phosphorylation of Src kinase and NR2B subunits as well as increased the surface expression of the NR2B subunit and increased NMDA component of the synaptic mEPSC. These results provide the first demonstration that astrocytes can affect neuronal excitability on a long time scale by regulating the surface expression of NMDA receptors through the activation of specific intracellular signaling pathways. FAU - Deng, Qiudong AU - Deng Q AD - Department of Neuroscience, Tufts University, Boston, Massachusetts 02111, USA. FAU - Terunuma, Miho AU - Terunuma M FAU - Fellin, Tommaso AU - Fellin T FAU - Moss, Stephen J AU - Moss SJ FAU - Haydon, Philip G AU - Haydon PG LA - eng GR - R01 DA025967-03/DA/NIDA NIH HHS/United States GR - R01 NS048045-05/NS/NINDS NIH HHS/United States GR - R01 NS048045/NS/NINDS NIH HHS/United States GR - R01 NS081986/NS/NINDS NIH HHS/United States GR - 5R01 NS048405/NS/NINDS NIH HHS/United States GR - 5R01NS037585/NS/NINDS NIH HHS/United States GR - R21 NS080064/NS/NINDS NIH HHS/United States GR - R01 NS051195/NS/NINDS NIH HHS/United States GR - R01 DA025967/DA/NIDA NIH HHS/United States GR - R01 NS037585/NS/NINDS NIH HHS/United States GR - 2R01 NS051195/NS/NINDS NIH HHS/United States GR - 5R01DA025967/DA/NIDA NIH HHS/United States GR - R01 NS051195-05/NS/NINDS NIH HHS/United States GR - R01 NS037585-14/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110504 PL - United States TA - Glia JT - Glia JID - 8806785 RN - 0 (Adenosine A1 Receptor Antagonists) RN - 0 (Enzyme Inhibitors) RN - 0 (Excitatory Amino Acid Agonists) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (NR2B NMDA receptor) RN - 0 (Receptor, Adenosine A1) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (SNARE Proteins) RN - 42HK56048U (Tyrosine) RN - 6384-92-5 (N-Methylaspartate) RN - 76326-31-3 (2-amino-5-phosphopentanoic acid) RN - 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid) RN - EC 2.7.10.2 (src-Family Kinases) RN - HG18B9YRS7 (Valine) SB - IM MH - Adenosine A1 Receptor Antagonists/pharmacology MH - Analysis of Variance MH - Animals MH - Astrocytes/*metabolism MH - Biotinylation/methods MH - Enzyme Inhibitors/pharmacology MH - Excitatory Amino Acid Agonists/pharmacology MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/drug effects/genetics MH - Gene Expression Regulation/drug effects/genetics MH - Immunoprecipitation/methods MH - In Vitro Techniques MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - N-Methylaspartate/pharmacology MH - Neurons/drug effects/metabolism MH - Patch-Clamp Techniques/methods MH - Phosphorylation/drug effects MH - Receptor, Adenosine A1/*metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - SNARE Proteins/genetics MH - Signal Transduction/drug effects/genetics/*physiology MH - Somatosensory Cortex/cytology MH - Tyrosine/metabolism MH - Valine/analogs & derivatives/pharmacology MH - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology MH - src-Family Kinases/*metabolism PMC - PMC3097531 MID - NIHMS285207 COIS- Any Conflict of Interest: none EDAT- 2011/05/06 06:00 MHDA- 2011/09/07 06:00 PMCR- 2012/07/01 CRDT- 2011/05/06 06:00 PHST- 2011/01/17 00:00 [received] PHST- 2011/03/29 00:00 [accepted] PHST- 2011/05/06 06:00 [entrez] PHST- 2011/05/06 06:00 [pubmed] PHST- 2011/09/07 06:00 [medline] PHST- 2012/07/01 00:00 [pmc-release] AID - 10.1002/glia.21181 [doi] PST - ppublish SO - Glia. 2011 Jul;59(7):1084-93. doi: 10.1002/glia.21181. Epub 2011 May 4.