Retina-driven dephosphorylation of the NR2A subunit correlates with faster NMDA receptor kinetics at developing retinocollicular synapses.
We describe a homeostatic mechanism that limits NMDA receptor currents in response to early light activation of a developing visual pathway. During the second postnatal week of rodent retinocollicular development, the Ca2+-activated phosphatase calcineurin (CaN) mediates a rapid, activity-induced shortening in the decay time of NMDA receptor (NMDAR) currents. We show that protein kinase A acts in opposition to CaN to maintain NMDAR currents with long decay times. The CaN-mediated change is coincident with the initial expression of the NMDAR subunit NR2A. Using NR2A knock-out mice and dialyzing neurons with a constitutively active CaN, we demonstrate that NR2A subunits are necessary for the effect of CaN on NMDAR current kinetics. In wild-type mice, Ser900 of NR2A, previously implicated in CaN-mediated glycine-independent desensitization, becomes chronically dephosphorylated by postnatal day 11 as NMDAR current decay times become faster. Pharmacologically disrupting early photoreceptor-driven activity in the retina eliminates the dephosphorylation of NR2A and prevents the shortening in NMDAR current decay time. These data suggest that the developmental onset of retinal activity increases CaN-mediated dephosphorylation of NR2A subunits newly incorporated into synaptic NMDARs of the superior colliculus, thereby providing a mechanism for the early and rapid reduction of NMDAR current decay time in visual neurons.
Townsend
Matthew
M
Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520, USA.
Liu
Yudong
Y
Constantine-Paton
Martha
M
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004594:Electrophysiology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D012160:Retina / Q000254:growth & development* / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology; D012694:Serine / Q000378:metabolism; D013477:Superior Colliculi / Q000254:growth & development* / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014795:Visual Pathways / Q000254:growth & development / Q000502:physiology
D019703:Calcineurin; D017868:Cyclic AMP-Dependent Protein Kinases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine