TY - JOUR
T1 - AMPA receptor-dependent, light-evoked D-serine release acts on retinal ganglion cell NMDA receptors
AU - Sullivan, Steve J.
AU - Miller, Robert F.
PY - 2012/8/15
Y1 - 2012/8/15
N2 - NMDA receptor (NMDAR) activation requires coincident binding of the excitatory neurotransmitter glutamate and a coagonist, either glycine or D-serine. Changes in NMDAR currents during neural transmission are typically attributed to glutamate release against a steady background of coagonist, excluding the possibility of coagonist release. AMPA receptor (AMPAR) stimulation evokes D-serine release, but it is unknown whether this is a physiological phenomenon capable of influencing synaptic responses. In this study, we utilized the intact retina to determine whether light-evoked synaptic activity in retinal ganglion cells (RGCs) is shaped by a dynamic pool of coagonist. The application of AMPAR antagonist abolished light-evoked NMDAR currents, which were rescued by adding coagonist to the bath. When NMDA was globally applied to RGCs via bath or picospritzing, the coagonist occupancy was also dependent on AMPARs but to a lesser extent than that observed during light responses, suggesting a difference in extrasynaptic coagonist regulation. By saturating the glutamate binding site of NMDARs, we were able to detect released coagonist reaching RGCs during light-evoked responses. Mutant mice lacking the D-serinesynthesizing enzyme serine racemase were deficient in coagonist release. Coagonist release in wild-type retinas was notably greater in ON than in OFF responses and depended on AMPARs. These findings suggest activity-dependent modulation of coagonist availability, particularly D-serine, and may add an extra dimension to NMDAR coincidence detection in the retina.
AB - NMDA receptor (NMDAR) activation requires coincident binding of the excitatory neurotransmitter glutamate and a coagonist, either glycine or D-serine. Changes in NMDAR currents during neural transmission are typically attributed to glutamate release against a steady background of coagonist, excluding the possibility of coagonist release. AMPA receptor (AMPAR) stimulation evokes D-serine release, but it is unknown whether this is a physiological phenomenon capable of influencing synaptic responses. In this study, we utilized the intact retina to determine whether light-evoked synaptic activity in retinal ganglion cells (RGCs) is shaped by a dynamic pool of coagonist. The application of AMPAR antagonist abolished light-evoked NMDAR currents, which were rescued by adding coagonist to the bath. When NMDA was globally applied to RGCs via bath or picospritzing, the coagonist occupancy was also dependent on AMPARs but to a lesser extent than that observed during light responses, suggesting a difference in extrasynaptic coagonist regulation. By saturating the glutamate binding site of NMDARs, we were able to detect released coagonist reaching RGCs during light-evoked responses. Mutant mice lacking the D-serinesynthesizing enzyme serine racemase were deficient in coagonist release. Coagonist release in wild-type retinas was notably greater in ON than in OFF responses and depended on AMPARs. These findings suggest activity-dependent modulation of coagonist availability, particularly D-serine, and may add an extra dimension to NMDAR coincidence detection in the retina.
KW - Extrasynaptic receptors
KW - Glycine
UR - http://www.scopus.com/inward/record.url?scp=84865106438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865106438&partnerID=8YFLogxK
U2 - 10.1152/jn.00264.2012
DO - 10.1152/jn.00264.2012
M3 - Article
C2 - 22592312
AN - SCOPUS:84865106438
SN - 0022-3077
VL - 108
SP - 1044
EP - 1051
JO - Journal of neurophysiology
JF - Journal of neurophysiology
IS - 4
ER -