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Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures

Abstract

Synaptic strength can be altered by a variety of pre- or postsynaptic modifications. Here we test the hypothesis that long-term depression (LTD) involves a decrease in the number of glutamate receptors that are clustered at individual synapses in primary cultures of hippocampal neurons. Similar to a prominent form of LTD observed in hippocampal slices, LTD in hippocampal cultures required NMDA receptor activation and was accompanied by a decrease in the amplitude and frequency of miniature excitatory postsynaptic currents. Immunocytochemical analysis revealed that induction of LTD caused a concurrent decrease in the number of AMPA receptors clustered at synapses but had no effect on synaptic NMDA receptor clusters. These results suggest that a subtype-specific redistribution of synaptic glutamate receptors contributes to NMDA receptor-dependent LTD.

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Figure 1: Stimulation of cultured hippocampal neurons for four minutes at 5 Hz results in LTD of mEPSC amplitude and frequency.
Figure 2: LTD requires NMDA receptor activation, postsynaptic depolarization and an increase in postsynaptic calcium.
Figure 3: Induction of LTD results in a decreased proportion of synapses that colocalize with GluR1 puncta.
Figure 4: Induction of LTD decreases the proportion of surface-expressed, synaptically localized GluR1 puncta.
Figure 5: Synaptic localization of the NMDA receptor NR1 subunit does not change after induction of LTD.
Figure 6: The proportion of NR1 puncta not associated with GluR1 puncta increases after LTD induction.
Figure 7: The AMPAR but not the NMDAR component of mEPSCs is reduced after the induction of LTD.

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Acknowledgements

We thank Sue Giller for preparation of the cultures. M.V.Z. and R.A.N. are supported by grants from the NIH. R.C.M. is supported by grants from the NIH and the Human Frontier Science Program and an Investigator Award from the McKnight Endowment Fund for Neuroscience. R.C.C. is supported by an NRSA from NINDS.

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Correspondence to Robert C. Malenka.

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Carroll, R., Lissin, D., Zastrow, M. et al. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nat Neurosci 2, 454–460 (1999). https://doi.org/10.1038/8123

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