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The Journal of Neuroscience, December 8, 2004, 24(49):11098-11107; doi:10.1523/JNEUROSCI.1207-04.2004

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Development/Plasticity/Repair
Retina-Driven Dephosphorylation of the NR2A Subunit Correlates with Faster NMDA Receptor Kinetics at Developing Retinocollicular Synapses

Matthew Townsend,¹ Yudong Liu,² and Martha Constantine-Paton³

¹Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520, ²Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, North Carolina 27599, and ³Departments of Biology and Brain and Cognitive Science and the McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

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.

Key words: NMDA; calcineurin; superior colliculus; development; visual; plasticity

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Received March 31, 2004; revised October 25, 2004; accepted October 30, 2004.

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