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AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.

ABSTRACT: The regulated trafficking of AMPA receptors (AMPARs) to synapses is thought to underlie the enhanced transmission in long-term potentiation (LTP), a cellular model of memory. However, there is controversy regarding the nonsynaptic site, either on the surface or intracellularly, from which AMPARs move into synapses during LTP. Using recombinant surface-fluorescent receptors in organotypic rat hippocampal slices, we show that the majority of AMPARs incorporated into synapses during LTP is from lateral diffusion of spine surface receptors containing GluR1, an AMPAR subunit. Following synaptic potentiation, AMPARs in intracellular pools containing GluR1 are driven to the surface primarily on dendrites. These exocytosed receptors likely serve to replenish the local extrasynaptic pool available for subsequent bouts of plasticity. These results clarify the role of intracellular and surface AMPARs during synaptic plasticity.

SUBMITTER: Makino H

PROVIDER: S-EPMC2999463 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.

Makino Hiroshi H Malinow Roberto R

Neuron 20091101 3

The regulated trafficking of AMPA receptors (AMPARs) to synapses is thought to underlie the enhanced transmission in long-term potentiation (LTP), a cellular model of memory. However, there is controversy regarding the nonsynaptic site, either on the surface or intracellularly, from which AMPARs move into synapses during LTP. Using recombinant surface-fluorescent receptors in organotypic rat hippocampal slices, we show that the majority of AMPARs incorporated into synapses during LTP is from lat ...[more]

PMID: 19914186

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Project description:The decrease in number of AMPA-type glutamate receptor (AMPAR) at excitatory synapses causes LTD, a cellular basis of learning and memory. The number of postsynaptic AMPARs is regulated by the balance of exocytosis and endocytosis, and enhanced endocytosis of AMPAR has been suggested to underlie the LTD expression. However, it remains unclear how endocytosis and exocytosis of AMPAR change during LTD. In this study, we addressed this question by analyzing exocytosis and endocytosis of AMPAR by imaging super-ecliptic pHlorin (SEP)-tagged AMPAR around postsynaptic structure formed directly on the glass surface in the hippocampal culture prepared from rat embryos of both sexes. Contrary to a prevailing view on the LTD expression by endocytosis enhancement, the LTD induction by NMDA application only transiently enhanced endocytosis of SEP-tagged GluA1 subunits of AMPAR, which was counteracted by simultaneous augmentation of exocytosis. As a result, soon after the start of the LTD induction (∼1 min), the surface AMPAR did not markedly decrease. Thereafter, the surface GluA1-SEP gradually decreased (2-5 min) and kept at a low level until the end of observation (>30 min). Surprisingly, this gradual and sustained decrease of surface AMPAR was accompanied not by the enhanced endocytic events of GluA1, but by the suppression of exocytosis. Together, our data highlight an unprecedented mechanism for the LTD expression by attenuation of exocytosis of AMPAR, but not by enhanced endocytosis, together with a reduction of postsynaptic AMPAR scaffolding protein PSD95.SIGNIFICANCE STATEMENT It has been generally assumed that LTD is expressed by enhancement of AMPAR endocytosis. Previous studies reported that endocytosis-related protein was involved in LTD and that significant amount of cell-surface AMPAR moved into intracellular compartments during LTD. Here, we report changes of cell-surface amount of AMPAR, and where and when individual exocytosis and endocytosis occurred during LTD. Cell-surface AMPAR gradually decreased in synchrony with suppression of exocytosis but not with enhancement of endocytosis. These results suggest that the decrease of cell-surface AMPAR amount during LTD was caused not by enhancement of endocytosis but rather by suppression of exocytosis, which revises current understanding of the expression mechanism of LTD.

Dataset Information

AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.

Publications

AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis.

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