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The Journal of Neuroscience, August 15, 2001, 21(16):6233-6244

Developmental Depression of Glutamate Neurotransmission by Chronic Low-Level Activation of NMDA Receptors

Jian Shi¹, Sandra M. Aamodt², Matthew Townsend^{1, 3}, and Martha Constantine-Paton¹

¹ Departments of Biology and Brain and Cognitive Science and The McGovern Brain Research Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and ² Department of Biology and ³ Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520

Slabs of slow-release plastic (Elvax) containing NMDA or solvent were implanted over the rat colliculus beginning on postnatal day 8 (P8). Whole-cell patch clamping in the superficial superior collicular layers (sSCs) from P10 to P21 demonstrated a severe decrease in spontaneous EPSC frequency after chronic NMDA treatment. The decrease was not attributable to an increase in GABA_A receptor-mediated inhibition and was present only when NMDA receptor (NMDAR) current was blocked by Mg²⁺. Analysis of miniature EPSCs indicated that many active sites on NMDA-treated neurons lacked functional AMPA and kainate receptor (AMPA/KAR) currents, and AMPA/KAR:NMDAR current ratios of evoked EPSCs were also significantly reduced. In addition, the normal downregulation of NMDAR decay time in sSC neurons at P11 was absent after NMDA treatment. Nevertheless, neither AMPA nor NMDA receptor subunit expression was altered by NMDA treatment, and experiments with the NMDAR antagonist ifenprodil suggested that incorporation of NR2A-containing NMDARs at the sSC synapses was unperturbed. Thus, disrupting but not blocking NMDARs suppresses the development of AMPA/KAR currents. The absence of the P11 NMDAR current downregulation is likely a secondary effect resulting from the reduction of AMPA/KAR function. Chronic agonist application reduces but does not eliminate NMDAR conductances. Therefore these data support an active role for NMDAR currents in synaptic development. Prolonged NMDA treatment in vivo, which couples reduced postsynaptic Ca²⁺ responses with normally developing afferent activity, produces a long-lasting synaptic depression and stalls glutamatergic synaptogenesis, suggesting that the correlation between robust NMDAR activation and afferent activity is an essential component during normal development.

Key words: NMDA receptors; AMPA receptors; development; synaptic competition; correlation detection; long-term depression; whole-cell patch clamping; superior colliculus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21166233-12$05.00/0

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