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

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Abstract
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 linearI–Vrelationships. 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.

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