Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting

Science ◽  
2018 ◽  
Vol 363 (6422) ◽  
pp. eaav1483 ◽  
Author(s):  
Ankit Awasthi ◽  
Binu Ramachandran ◽  
Saheeb Ahmed ◽  
Eva Benito ◽  
Yo Shinoda ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Plasma Membranes ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Receptor Internalization ◽  
Synaptic Plasma Membranes ◽  
Calcium Sensing ◽  
Term Potentiation

Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.

scholarly journals GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 715-720 ◽  
Author(s):  
Fabrice Duprat ◽  
Michael Daw ◽  
Wonil Lim ◽  
Graham Collingridge ◽  
John Isaac
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Protein Protein Interactions ◽  
Term Potentiation

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

A selective LTP of NMDA receptor-mediated currents induced by anoxia in CA1 hippocampal neurons

1993 ◽  
Vol 70 (5) ◽  
pp. 2045-2055 ◽  
Author(s):  
V. Crepel ◽  
C. Hammond ◽  
P. Chinestra ◽  
D. Diabira ◽  
Y. Ben-Ari
Keyword(s):  
Nmda Receptor ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Peak Amplitude ◽  
Excitatory Postsynaptic Potential ◽  
Physiological Concentration ◽  
Term Potentiation

1. The possibility of long-lasting modifications of glutamatergic responses after anoxic-aglycemic (AA) episodes was investigated in CA1 hippocampal neurons of adult slices. Bicuculline (10 microM) was continuously bath applied to block GABAA receptor-mediated currents. AA episodes were induced by brief (1.30-3 min) perfusions with a glucose free artificial-cerebro-spinal-fluid (ACSF) saturated with 95% N2-5% CO2. 2. In presence of (0.6 mM) Mg2+ and a low concentration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1 microM), the Schaffer collateral field EPSPs consisted of an early AMPA receptor-mediated component and a late N-methyl-D-aspartate (NMDA) receptor-mediated component. The former was blocked by (10 microM) CNQX and the latter by (50) microM D-2-amino-5-phosphonovalerate (D-APV). The AA episode induced a selective long-term potentiation (LTP) of the NMDA receptor-mediated component [+70 +/- 13% (mean +/- SE), P < or = 0.008, n = 9] without affecting significantly the AMPA receptor-mediated component (+2 +/- 4, P < or = 0.86 n = 9). This selective LTP is due to an enhanced efficacy of synaptic transmission and will be referred to as anoxic LTP. 3. In slices perfused with an ACSF containing a physiological concentration of (1.3 mM) Mg2+ and no CNQX, the intracellularly recorded excitatory postsynaptic potential (EPSP) was mixed (AMPA/NMDA) at -65 mV and exclusively mediated by AMPA receptors at -100 mV. At -65 mV, the AA episode induced a persistent potentiation of the EPSP (peak amplitude potentiated by 43 +/- 6%, P < or = 0.008, n = 9, 1 h after return to control ACSF). This potentiated component of the EPSP was fully sensitive to (50 microM) D-APV. The CNQX-sensitive AMPA receptor-mediated component was not affected by the AA episode (-5.7 +/- 6%, P < or = 0.123, n = 9). Furthermore, at -100 mV a large APV-sensitive component appeared after the AA episode (+58 +/- 18% of the peak amplitude, P < or = 0.018, n = 9). Therefore, the AA episode induced a selective LTP of the NMDA receptor-mediated component of the EPSP. 4. A robust LTP (+50.0 +/- 7.5%, P < or = 0.008, n = 12) of the NMDA receptor-mediated intracellular EPSP was also observed when AMPA receptors were fully and continuously blocked by (15 microM) CNQX.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pojeong Park ◽  
John Georgiou ◽  
Thomas M. Sanderson ◽  
Kwang-Hee Ko ◽  
Heather Kang ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Single Channel ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Theta Burst Stimulation ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Necessary And Sufficient ◽  
Theta Burst

AbstractLong-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here, we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involves purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA is activated, results in LTP that is associated with a transient increase in γ (LTPγ), caused by the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII is necessary and sufficient for LTPN whilst PKA is additionally required for LTPγ. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.

AMPA Silencing Is a Prerequisite for Developmental Long-Term Potentiation in the Hippocampal CA1 Region

2008 ◽  
Vol 100 (5) ◽  
pp. 2605-2614 ◽  
Author(s):  
Therése Abrahamsson ◽  
Bengt Gustafsson ◽  
Eric Hanse
Keyword(s):  
Developmental Stages ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Silent Synapses ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca3

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) unsilencing is an often proposed expression mechanism both for developmental long-term potentiation (LTP), involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3–CA1 connection naïve (nonstimulated) synapses are AMPA signaling and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test-pulse synaptic activation (AMPA silencing). To investigate to what extent LTPs at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus this early, or developmental, LTP is nothing more than an unsilencing (dedepression) and stabilization of the AMPA signaling that was lost by the prior AMPA silencing. This dedepression and stabilization of AMPA signaling was mimicked by the presence of the protein kinase A activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a “genuine” potentiation (as opposed to a dedepression) not explained by unsilencing and stabilization of AMPA-labile synapses. This “genuine,” or mature, LTP rose from close to nothing of total LTP prior to postnatal day (P)13, to about 70% of total LTP at P16, and to about 90% of total LTP at P30. Developmental LTP, by stabilization of AMPA-labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.

scholarly journals Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Javier Díaz-Alonso ◽  
Wade Morishita ◽  
Salvatore Incontro ◽  
Jeffrey Simms ◽  
Julia Holtzman ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Morris Water Maze ◽  
Ampa Receptor ◽  
Water Maze ◽  
Long Term Potentiation ◽  
Receptor Subunit ◽  
Terminal Domain ◽  
Term Potentiation ◽  
Ampa Receptor Subunit

We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs.

scholarly journals Phosphorylation of the AMPAR-TARP Complex in Synaptic Plasticity

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 40 ◽  
Author(s):  
Joongkyu Park
Keyword(s):  
Synaptic Plasticity ◽  
Drug Addiction ◽  
Ampa Receptor ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Regulatory Proteins ◽  
Cellular Models ◽  
Brain Functions ◽  
Term Potentiation

Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity.

Estrogenic Regulation of Synaptic Actin Proteins and Plasticity

2020 ◽  
pp. 69-82
Author(s):  
Enikö A. Kramár
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Signaling Cascade ◽  
Term Potentiation ◽  
Estrogenic Regulation ◽  
Estradiol Levels

Estrogens are rapid and potent facilitators of synaptic plasticity in the adult brain; however, the steps that link estrogens to factors that regulate synaptic strength remain unclear. The present chapter will first review the acute effects of 17β‎-estradiol on synaptic transmission and long-term potentiation (LTP). It will then describe a synaptic model used to study the substrates of LTP and provide evidence for the ability of estradiol to rapidly engage a selective actin signaling cascade associated with the consolidation of LTP. Finally, it will be shown that chronic reductions in estradiol levels disrupt LTP and actin dynamics but can be reversed by acute infusions of the hormone. It is concluded here that estradiol can promote learning-related plasticity by modifying the synaptic cytoskeleton.

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