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The Journal of Neuroscience, October 24, 2007, 27(43):11651-11662; doi:10.1523/JNEUROSCI.2671-07.2007

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Cellular/Molecular
Developmental Expression of Ca²⁺-Permeable AMPA Receptors Underlies Depolarization-Induced Long-Term Depression at Mossy Fiber–CA3 Pyramid Synapses

Michelle T.-W. Ho,^1,3 Kenneth A. Pelkey,¹ Lisa Topolnik,⁴ Ronald S. Petralia,² Kogo Takamiya,⁵ Jun Xia,⁵ Richard L. Huganir,⁵ Jean-Claude Lacaille,⁴ and Chris J. McBain¹

¹National Institute of Child Health and Human Development and ²National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, ³Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, The People's Republic of China, ⁴Département de Physiologie, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada H3C 3J7, and ⁵Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205

Correspondence should be addressed to Kenneth A. Pelkey, Laboratory on Cellular and Synaptic Neurophysiology, Building 35, Room 3C705, National Institute of Child Health and Human Development, Bethesda, MD 20892. Email: pelkeyk2{at}mail.nih.gov

Many central excitatory synapses undergo developmental alterations in the molecular and biophysical characteristics of postsynaptic ionotropic glutamate receptors via changes in subunit composition. Concerning AMPA receptors (AMPARs), glutamate receptor 2 subunit (GluR2)-containing, Ca²⁺-impermeable AMPARs (CI-AMPARs) prevail at synapses between mature principal neurons; however, accumulating evidence indicates that GluR2-lacking, Ca²⁺-permeable AMPARs (CP-AMPARs) contribute at these synapses early in development. Here, we used a combination of imaging and electrophysiological recording techniques to investigate potential roles for CP-AMPARs at developing hippocampal mossy fiber–CA3 pyramidal cell (MF–PYR) synapses. We found that transmission at nascent MF–PYR synapses is mediated by a mixed population of CP- and CI-AMPARs as evidenced by polyamine-dependent inwardly rectifying current–voltage (I–V) relationships, and partial philanthotoxin sensitivity of synaptic events. CP-AMPAR expression at MF–PYR synapses is transient, being limited to the first 3 postnatal weeks. Moreover, the expression of CP-AMPARs is regulated by the PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-containing protein interacting with C kinase 1 (PICK1), because MF–PYR synapses in young PICK1 knock-out mice are philanthotoxin insensitive with linear I–V relationships. Strikingly, MF–PYR transmission via CP-AMPARs is selectively depressed during depolarization-induced long-term depression (DiLTD), a postsynaptic form of MF–PYR plasticity observed only at young MF–PYR synapses. The selective depression of CP-AMPARs during DiLTD was evident as a loss of postsynaptic CP-AMPAR-mediated Ca²⁺ transients in PYR spines and reduced rectification of MF–PYR synaptic currents. Preferential targeting of CP-AMPARs during DiLTD is further supported by a lack of DiLTD in young PICK1 knock-out mice. Together, these findings indicate that the transient participation of CP-AMPARs at young MF–PYR synapses dictates the developmental window to observe DiLTD.

Key words: LTD; GluR2; mossy fiber; hippocampus; synapse development; calcium

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Received June 12, 2007; revised Aug. 28, 2007; accepted Sept. 3, 2007.

Correspondence should be addressed to Kenneth A. Pelkey, Laboratory on Cellular and Synaptic Neurophysiology, Building 35, Room 3C705, National Institute of Child Health and Human Development, Bethesda, MD 20892. Email: pelkeyk2{at}mail.nih.gov

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