Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Strengthening Synaptic Connections by NMDA for Long-Term Potentiation (LTP)


Nature  544, 316–321 (20 April 2017)

Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP

Dick Wu,

Department of Molecular & Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California 94305, USA

Nancy Pritzker Laboratory, Stanford University Medical School, Stanford, California 94305, USA

Department of Psychiatry & Behavioral Sciences, Stanford University Medical School, Stanford, California 94305, USA

Department of Neurosurgery, Stanford University Medical School, Stanford, California 94305, USA


Strengthening of synaptic connections by NMDA (N-methyl-d-aspartate) receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During the induction of NMDA-receptor-dependent LTP, Ca2+ influx stimulates recruitment of synaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, thereby strengthening synapses. How Ca2+ induces the recruitment of AMPA receptors remains unclear. Here we show that, in the pyramidal neurons of the hippocampal CA1 region in mice, blocking postsynaptic expression of both synaptotagmin-1 (Syt1) and synaptotagmin-7 (Syt7), but not of either alone, abolished LTP. LTP was restored by expression of wild-type Syt7 but not of a Ca2+-binding-deficient mutant Syt7. Blocking postsynaptic expression of Syt1 and Syt7 did not impair basal synaptic transmission, reduce levels of synaptic or extrasynaptic AMPA receptors, or alter other AMPA receptor trafficking events. Moreover, expression of dominant-negative mutant Syt1 which inhibits Ca2+-dependent presynaptic vesicle exocytosis, also blocked Ca2+-dependent postsynaptic AMPA receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic Syt1 and Syt7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA receptors during LTP, and thereby delineate a simple mechanism for the recruitment of AMPA receptors that mediates LTP.

Synapses connect the neurons in the brain into vast communicating networks composed of overlapping circuits that are highly dynamic owing to synaptic plasticity. Arguably the most compelling form of such plasticity is NMDA receptor (NMDAR)-dependent LTP. NMDAR-dependent LTP is crucial for the formation of neural circuits and for the restructuring of neural circuits during learning and memory. NMDAR-dependent LTP operates widely in the brain, but has been most extensively studied at CA3–CA1 Schaffer collateral synapses in the hippocampus.

During LTP induction, coincident stimulation of presynaptic inputs on a postsynaptic neuron    gates a postsynaptic influx of Ca2+ through NMDARs.    Intracellular Ca2+ then causes an increase in postsynaptic levels of AMPA receptors (AMPARs), thereby enhancing synaptic strength.

The mechanisms that increase postsynaptic AMPAR levels during LTP are not completely understood, although it has been suggested that the Ca2+-dependent capture of extrasynaptic AMPARs by postsynaptic specializations is the most critical step. However, blocking postsynaptic membrane fusion impairs AMPAR recruitment during LTP, suggesting that Ca2+-dependent AMPAR exocytosis is also involved. Thus, two major questions arise: what molecular mechanisms deliver AMPARs to synapses during LTP, and how are these mechanisms regulated by Ca2+?

In considering these questions, we focused on the potential role of postsynaptic synaptotagmins in LTP because synaptotagmins are well established Ca2+ sensors for Ca2+-triggered exocytosis, and because complexin, a co-factor for synaptotagmins in exocytosis, is also postsynaptically essential for LTP. Among synaptotagmins, synaptotagmin-1 (Syt1) acts as the main Ca2+ sensor for fast presynaptic vesicle exocytosis, whereas synaptotagmin-7 (Syt7) functions as the predominant Ca2+ sensor for a slower form of exocytosis. Moreover, Syt1 and Syt7 are redundantly essential for Ca2+-stimulated chromaffin granule exocytosis, which exhibits a time course similar to that of LTP induction. Here, we show that Syt1 and Syt7 act as essential but redundant postsynaptic Ca2+ sensors for AMPAR exocytosis during LTP, uncovering a simple mechanism for the Ca2+-dependent recruitment of AMPARs during LTP.

Using multiple in vivo and in vitro manipulations of postsynaptic Syt1 and Syt7, we show that NMDAR-dependent LTP requires Syt1 or Syt7 as functionally redundant Ca2+ sensors for AMPAR exocytosis. Our results imply that Ca2+-triggered AMPAR exocytosis is a critical step in LTP and that Ca2+-regulated membrane traffic is governed by similar mechanisms in presynaptic and postsynaptic compartments, revealing an unexpectedly economical organization of synapses. Two independent lines of evidence directly show that Syt1 and Syt7 act as Ca2+ sensors for AMPAR exocytosis during LTP. First, a mutation in Syt7 that abolishes Ca2+ binding but does not produce a dominant-negative effect fails to rescue LTP. Second, a mutation in Syt1 that abolishes Ca2+ binding and renders it dominant-negative for Ca2+ sensing but not for Ca2+-independent exocytosis also blocks LTP. CaM kinase IIα, which is activated by Ca2+, is also essential for LTP, raising the question of how Ca2+-sensing by synaptotagmins and CaM kinase IIα work together in LTP. Several mechanisms are conceivable; for example, CaM kinase IIα might activate exocytosis, possibly through phosphorylation of Syt1 and Syt7, or CaM kinase IIα may play a role in stably capturing AMPARs in postsynaptic sites. It seems likely that Ca2+-induced AMPAR exocytosis during LTP is perisynaptic, with subsequent lateral diffusion of perisynaptic AMPARs into the postsynaptic density, but direct exocytosis of AMPAR vesicles into the postsynaptic membrane cannot at present be ruled out.

The unexpected discovery of a critical role of postsynaptic synaptotagmins as Ca2+-sensors for LTP provides new insight into synaptic plasticity. Showing that presynaptic and postsynaptic mechanisms share critical features renders LTP a simple and economical process, as would be expected for a universal mechanism involved in circuit plasticity.

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