The AMPA Receptor Code of Synaptic Plasticity

May combine two claims.

CNIH and TARPs likely compete for the same AMPAR binding sites, and one possible function of CNIH is to regulate the stoichiometry of TARP interaction, tuning the channel properties of associated AMPARs.

“CNIH and TARPs likely compete for the same AMPAR binding sites (Straub and Tomita, 2012, Herring et al., 2013), and so one possible function of CNIH is to regulate the stoichiometry of TARP interaction, tuning the channel properties of the associated AMPARs.”

• cites Straub and Tomita, 2012 sourceSupported
• cites Herring et al., 2013 sourceDisputed

  The Results section (‘TARP γ-8 reverses…’; page unavailable) says that unchanged γ-8/AMPAR stoichiometry strongly argues CNIH-2 does not displace γ-8 and that the two can co-occupy GluA1 subunits. The Discussion (‘A model for the interaction…’; page unavailable) proposes four γ-8 molecules on the receptor combinations examined, contrary to CNIH regulating TARP stoichiometry by competing for those sites. The paper does report a different, subunit-specific interaction: γ-8 prevents CNIH from interacting with non-GluA1 subunits. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

AMPARs are highly dynamic, undergoing continuous endocytosis, exocytosis, lateral diffusion, reversible trapping at PSD, and modifications in channel properties.

“AMPARs are highly dynamic, undergoing continuous endocytosis, exocytosis, lateral diffusion in the plane of the membrane, reversible trapping at synapses at the post-synaptic density (PSD), and modifications in channel properties (Opazo et al., 2012, Huganir and Nicoll, 2013, Malinow and Malenka, 2002).”

• cites Opazo et al., 2012 sourceNot checked — no full text of the source
• cites Huganir and Nicoll, 2013 sourceSupported
• cites Malinow and Malenka, 2002 sourceNot checked — no full text of the source

May combine two claims.

Ubiquitination and phosphorylation of GluA1 reciprocally inhibit each other, indicating complex cross talk of GluA1 PTMs may regulate LTP expression.

“Interestingly, ubiquination and phosphorylation of GluA1 reciprocally inhibit each other indicating that a complex cross talk of GluA1 PTMs may regulate LTP expression (Guntupalli et al., 2017).”

• cites Guntupalli et al., 2017 sourcePartly supported

  The Results section, “The cross-talk between GluA1 phosphorylation and ubiquitination” (page unavailable), supports reciprocal inhibition at GluA1 Ser-845: ubiquitin-deficient mutants showed increased phosphorylation, while an S845D phosphomimetic showed reduced ubiquitination. The paper links this cross-talk to AMPA receptor trafficking and surface expression, but does not establish that it regulates LTP expression. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

During hippocampal LTP, PKC is activated to increase GluA1 S818 phosphorylation; peptide mimicking phospho-GluA1 S818 or shRNA-mediated knock-down of 4.1N both lead to decay of hippocampal LTP back to baseline, suggesting PKC/4.1N mediated increase in GluA1 exocytosis is necessary to maintain LTP.

“During hippocampal LTP, PKC is activated to increase GluA1 S818 phosphorylation and a peptide mimicking phospho-GluA1 S818 or shRNA-mediated knock-down of 4.1N both lead to decay of hippocampal LTP back to baseline, suggesting that the PKC/4.1N mediated increase in GluA1 exocytosis is necessary to maintain LTP (Lin et al., 2009, Boehm et al., 2006).”

• cites Lin et al., 2009 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Boehm et al., 2006 sourceNot checked — no full text of the source

May combine two claims.

AMPARs are substrates for PKA and PKG (GluA1 S845; GluA4 S842), PKC (GluA1 S818/S831/T840; GluA2 S863/S880), CaMKII (GluA1 S567/S831), Casein kinase II (GluA1 S579; GluA2 S588), PAK3 (GluA1 S863), and Src family tyrosine kinase (GluA2 Y876).

“AMPARs are substrates for cAMP-dependent kinase (PKA) and cGMP-dependent kinase (PKG) (GluA1 S845; GluA4 S842), protein kinase C (PKC) (GluA1 S818/S831/T840; GluA2 S863/S880), Ca++/calmodulin dependent kinase II (CaMKII) (GluA1 S567/S831), Casein kinase II (GluA1 S579; GluA2 S588), PAK3 (GluA1 S863), and Src family tyrosine kinase (GluA2 Y876) (Roche et al., 1996, Barria et al., 1997a, Barria et”

• cites Roche et al., 1996 sourcePartly supported

  The Phosphorylation of Ser-845 and Ser-831 sections support PKA phosphorylation of GluR1 (GluA1) S845 and PKC phosphorylation of GluR1 S831. The cited paper also discusses CaMKII phosphorylation of GluR1 generally, but our copy does not establish the sentence’s other specified kinase–site pairings, including PKG, casein kinase II, PAK3, and Src pairings. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Barria et al., 1997aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Barria et al., 1997bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

CP-AMPARs have faster decay kinetics but large conductance, enhancing synaptic transmission, and may activate unique Ca2+-sensitive signaling pathways which lead to opening of a metaplastic state, in which synapses become primed for LTD or LTP.

“These receptors have faster decay kinetics but large conductance, enhancing synaptic transmission, and may activate unique Ca2+-sensitive signaling pathways which lead to an opening of a metaplastic state, in which synapses become primed for LTD or LTP (Clem and Huganir, 2010, Sanderson et al., 2016).”

• cites Clem and Huganir, 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sanderson et al., 2016 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

GluA1 directly interacts with the cytoskeletal scaffold protein 4.1N through the C-terminal juxtamembrane region, and this interaction promotes activity-dependent exocytosis of GluA1 from intracellular endosomes.

“GluA1 directly interacts with the cytoskeletal scaffold protein 4.1N through the C-terminal juxtamembrane region, and this interaction promotes activity-dependent exocytosis of GluA1 from intracellular endosomes (Lin et al., 2009, Anggono and Huganir, 2012).”

• cites Lin et al., 2009 sourcePartly supported

  The Introduction and Results describe 4.1N binding to the membrane-proximal region of GluR1 (GluA1) and its role in activity-dependent insertion at the extrasynaptic surface. The Introduction says AMPARs are *thought* to originate from recycling endosomes, but the paper does not establish that the 4.1N-dependent GluR1 insertion events specifically come from intracellular endosomes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Anggono and Huganir, 2012 sourceSupported

May combine two claims.

PKA-mediated phosphorylation of GluA1 S845 promotes surface trafficking of the receptor, lowering the threshold needed to induce LTP, but additional signaling from CaMKII is needed to promote GluA1 targeting to the PSD for maximal LTP.

“These findings, together with several previous studies, support a model where PKA-mediated phosphorylation of GluA1 S845 promotes the surface trafficking of the receptor, lowering the threshold needed to induce LTP, however, additional signaling from CaMKII is needed to promote GluA1 targeting to the PSD for maximal LTP (Figure 1) (Sun et al., 2005, Oh et al., 2006, Esteban et al., 2003).”

• cites Sun et al., 2005 sourcePartly supported

  The Discussion reports that D1–PKA signaling increases extrasynaptic GluR1 surface expression and that CaMKII is also needed for synaptic delivery. The section on D1 receptor stimulation shows that pretreatment enables a normally subthreshold glycine concentration to increase synaptic GluR1 incorporation. Our copy does not establish phosphorylation specifically at S845, directly measure a lowered LTP-induction threshold, or address maximal LTP or PSD targeting. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Oh et al., 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Esteban et al., 2003 sourceNot checked — no full text of the source

May combine two claims.

NMDAR-dependent LTP requires Ca2+ influx leading to activation of CaMKII/PKC which directly phosphorylate GluA1 S831, increasing GluA1 single channel conductance and promoting GluA1 targeting to the PSD.

“NMDAR-dependent LTP requires Ca2+ influx leading to activation of CaMKII/PKC which directly phosphorylate GluA1 S831, increasing GluA1 single channel conductance and promoting GluA1 targeting to the PSD (Mammen et al., 1997, Barria et al., 1997a, Derkach et al., 1999, Kristensen et al., 2011, Barria et al., 1997b).”

• cites Mammen et al., 1997 sourceNot checked — no full text of the source
• cites Barria et al., 1997aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Derkach et al., 1999 sourcePartly supported

  The Abstract and Results report that CaMKII phosphorylation of GluR1 (GluA1) at Ser-831 increases the contribution of higher single-channel conductance states. The paper also says PKC phosphorylates Ser-831, but treats its effect on conductance as presumptive. It does not establish NMDAR dependence or show that this phosphorylation promotes GluA1 targeting to the postsynaptic density. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

NMDAR-dependent LTP is the result of increased AMPAR density in the post-synaptic membrane and/or single channel conductance of the AMPAR.

“The major form of LTP identified in the brain, NMDAR-dependent LTP, is the result of increased AMPAR density in the post-synaptic membrane and/or single channel conductance of the AMPAR (Huganir and Nicoll, 2013, Herring and Nicoll, 2016, Poncer et al., 2002, Benke et al., 1998).”

• cites Huganir and Nicoll, 2013 sourceSupported
• cites Herring and Nicoll, 2016 sourceNot checked — no full text of the source
• cites Poncer et al., 2002 sourcePartly supported

  The introductory passage and Discussion describe increased synaptic AMPAR number and channel conductance as mechanisms associated with LTP in CA1 hippocampal neurons. The paper does not establish that these mechanisms explain NMDAR-dependent LTP throughout the brain; its own experiments test whether activated CaMKII mimics LTP-related effects in CA1 neurons. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

TARPs stabilize AMPARs both on the cell surface and at synapses, and loss of TARPs results in decreased AMPAR expression, suggesting TARPless AMPARs become unstable.

“TARPs have been shown to stabilize AMPARs both on the cell surface and at synapses (Bats et al., 2007, Sheng et al., 2018), and loss of TARPs results in decreased AMPAR expression, suggesting that “TARPless” AMPARs become unstable (Fukaya et al., 2006, Chen et al., 2000).”

• cites Bats et al., 2007 sourceNot checked — no full text of the source
• cites Sheng et al., 2018 sourcePartly supported

  The Discussion reports that the PDZ ligand of TARP γ-8 is essential for moving surface AMPARs to synapses, supporting the synaptic part of the claim. The Results report equal surface AMPAR currents with intact γ-8 and a PDZ-motif-deficient mutant; the paper does not establish that TARPs stabilize AMPARs on the cell surface. The decreased-expression and instability clause is attributed to other citations, not Sheng et al. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Fukaya et al., 2006 sourcePartly supported

  The Results section (‘Selective reduction of hippocampal AMPA receptors in γ-8-KO mice’; page unavailable) reports substantially lower hippocampal AMPA receptor levels after γ-8 deletion. The Discussion (‘Differences between the present and preceding studies’; page unavailable) suggests that receptors redistributed toward cell bodies are presumably degraded. The study does not establish that those receptors lack all TARPs or directly show that TARP-free receptors are unstable. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

TARPs and CNIH2/3 regulate AMPAR channel properties and cellular and synaptic trafficking.

“TARPs and CNIH2/3 regulate AMPAR channel properties and cellular and synaptic trafficking (Straub and Tomita, 2012, Maher et al., 2017, Jacobi and von Engelhardt, 2017).”

• cites Straub and Tomita, 2012 sourcePartly supported

  The Conclusions state that TARPs modulate both AMPAR trafficking and channel properties, while CNIH2/3 modulate AMPAR channel properties. The section “Roles of CNIH2/3 in regulating AMPA receptors in the brain” reports enhanced AMPAR surface expression in heterologous cells but says whether CNIH2/3 promote trafficking in hippocampal neurons remains unresolved. Thus the claim overstates CNIH2/3’s established role in synaptic trafficking. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Maher et al., 2017 sourceNot checked — no full text of the source
• cites Jacobi and von Engelhardt, 2017 sourceNot checked — no full text of the source

May combine two claims.

The Granger et al. method would dramatically disrupt the composition of synapses and may not reflect the physiological mechanisms underlying LTP expression.

“This method would dramatically disrupt the composition of synapses and may not reflect the physiological mechanisms underlying LTP expression (Sheng et al., 2013).”

• cites Sheng et al., 2013 sourceSupported

May combine two claims.

Phosphorylation of S845 increases single channel open probability and promotes GluA1 targeting or retention to the cell surface.

“Phosphorylation of S845 increases single channel open–probability and also promotes GluA1 targeting or retention to the cell surface (Banke et al., 2000, Oh et al., 2006, Man et al., 2007).”

• cites Banke et al., 2000 sourcePartly supported

  The Discussion states that phosphorylation of GluR1 Ser845 by PKA appears to increase peak open probability, supporting the first part of the sentence. The passages on recombinant receptor function and the additional search do not establish that Ser845 phosphorylation promotes targeting or retention at the cell surface. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Oh et al., 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Man et al., 2007 sourceNot checked — no full text of the source

May combine two claims.

TARP γ-8 effectively prevented CNIH2/3 interaction with GluA2/3 heteromeric receptors, suggesting CNIH proteins may control the subunit composition of synaptic AMPARs.

“TARP γ-8 effectively prevented CNIH2/3 interaction with GluA2/3 heteromeric receptors suggesting that CNIH proteins may control the subunit composition of synaptic AMPARs (Herring et al., 2013).”

• cites Herring et al., 2013 sourcePartly supported

  The Discussion’s model for GluA2A3 heteromers says the receptors did not coimmunoprecipitate CNIH-2 and proposes that they contain γ-8 but no CNIH, supporting the proposed link to synaptic AMPAR subunit composition. It calls γ-8’s inhibition of CNIH interaction with GluA3 speculative, however, so the claim presents that mechanism more definitively than the paper does. Page numbers were not available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

The presence of perisynaptic CP-AMPARs as well as their recruitment to synapses requires signaling from PKA and the S845 phosphorylation site.

“The presence of perisynaptic CP-AMPARs as well as their recruitment to synapses requires signaling from PKA and the S845 phosphorylation site (He et al., 2009, Clem and Huganir, 2010, Sanderson et al., 2016).”

• cites He et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Clem and Huganir, 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sanderson et al., 2016 sourcePartly supported

  The Introduction reports PKA-dependent recruitment of CP-AMPARs to synapses during LTD induction, and the Discussion says a perisynaptic CP-AMPAR pool was absent in S845A mice (page numbers unavailable). The paper does not establish that PKA signaling is required for the presence of that perisynaptic pool; it also acknowledges uncertainty about whether recruitment is physical or functional. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

S-nitrosylation of GluA1 C875 by nNOS enhances phosphorylation of GluA1 S831 by CaMKII, suggesting an additional synergistic relationship between S831 phosphorylation and C875 nitrosylation.

“S-nitrosylation of GluA1 C875 by nNOS was found to enhance the phosphorylation of GluA1 S831 by CaMKII (Figure 1) (Selvakumar et al., 2013), suggesting an additional synergistic relationship between S831 phosphorylation and C875 nitrosylation.”

• cites Selvakumar et al., 2013 sourcePartly supported

  The Results and Discussion report that nNOS-derived NO nitrosylates GluA1 at C875 and facilitates S831 phosphorylation. However, the direct phosphorylation experiments described in the Results used PKC stimulation; the CaMKII experiments measured changes in channel conductance, not a direct enhancement of CaMKII-mediated S831 phosphorylation by C875 nitrosylation. Page numbers were not available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

All four AMPAR subunits are ubiquitinated, with major sites on GluA1 and GluA2 mapped to GluA1 K868 and GluA2 K870/K882.

“All four AMPAR subunit are also ubiquitinated. The major sites of ubiquitination on GluA1 and GluA2 have been mapped to GluA1 K868 and GluA2 K870/K882 (Widagdo et al., 2015, Widagdo et al., 2017, Lussier et al., 2015).”

• cites Widagdo et al., 2015 sourceSupported
• cites Widagdo et al., 2017 sourceSupported
• cites Lussier et al., 2015 sourcePartly supported

  The Ubiquitination section (page not provided) reports that proteomic studies identified all four AMPAR subunits, GluA1–4, as ubiquitinated. Our copy does not identify GluA1 K868 or GluA2 K870/K882 as major ubiquitination sites; searches for those residues found no supporting passage. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Phosphorylation of the TARP C-terminus reduces interaction with membrane lipids and facilitates interaction with PSD95, serving to trap the TARP/AMPAR complex with the PSD.

“Phosphorylation reduces the interaction with membrane lipids and facilitates interaction with PSD95, serving to trap the TARP/AMPAR complex with the PSD (Opazo et al., 2012, Bats et al., 2007, Sheng et al., 2018).”

• cites Opazo et al., 2012 sourceNot checked — no full text of the source
• cites Bats et al., 2007 sourceNot checked — no full text of the source
• cites Sheng et al., 2018 sourcePartly supported

  The Discussion (page not available) proposes that PSD-95 can capture AMPAR/TARP complexes through their PDZ ligands, supporting the trapping portion of the claim. It does not say that phosphorylation of the TARP C-terminus reduces membrane-lipid binding or facilitates PSD-95 binding; the phosphorylation described in that model is of synGAP. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Cerebellar LTD, NMDAR-dependent LTD, and mGluR-dependent LTD are expressed by a decrease in synaptic AMPAR content.

“Several major forms of LTD described in the brain including, cerebellar LTD and NMDAR-dependent and mGluR-dependent LTD, are expressed by a decrease in synaptic AMPAR content (Huganir and Nicoll, 2013).”

• cites Huganir and Nicoll, 2013 sourcePartly supported

  The NMDAR-Dependent LTD section says there is general consensus that LTD-related depression reflects a loss of synaptic AMPARs. The Cerebellar LTD section describes AMPAR endocytosis and retention of GluA2 inside the cell. Although it says mGluR1 activation induces cerebellar LTD, the passages do not establish the claim for mGluR-dependent LTD as a separately named form. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

LTP in cerebellar Purkinje neurons and cerebellar-dependent adaptation of the vestibulo-ocular reflex both depend on GluA3- but not GluA1-containing AMPARs.

“Recently, it has been found that LTP in cerebellar Purkinje neurons as well as cerebellar-dependent adaptation of the vestibulo-ocular reflex both depend on GluA3- but not GluA1-containing AMPARs (Gutierrez-Castellanos et al., 2017).”

• cites Gutierrez-Castellanos et al., 2017 sourceSupported

May combine two claims.

PICK1 via its BAR-domain can either promote invagination of the plasma membrane or direct GluA2 to regions of invagination where clathrin-mediated endocytosis occurs.

“Via its BAR-domain, PICK1 can either promote the invagination of the plasma membrane or direct GluA2 to regions of invagination where clathrin-mediated endocytosis occurs (Xia et al., 2000, Fiuza et al., 2017).”

• cites Xia et al., 2000 sourceNot checked — no full text of the source
• cites Fiuza et al., 2017 sourcePartly supported

  The Introduction and Discussion (‘AMPAR clustering at CCPs’; page not provided) support PICK1-dependent targeting of GluA2-containing receptors to clathrin-coated endocytic sites, with AP2 binding at or adjacent to PICK1’s BAR domain. They do not establish that PICK1’s BAR domain itself promotes plasma-membrane invagination; the paper instead describes its interaction with dynamin and stimulation of dynamin polymerization. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

GluA3-containing receptors are mostly inert under basal conditions due to a very low open probability, although they are robustly targeted to synapses.

“Here it was shown GluA3 containing receptors are mostly inert under basal conditions due to a very low-open probability, although these receptors are robustly targeted to synapses (Renner et al., 2017).”

• cites Renner et al., 2017 sourceSupported

May combine two claims.

Genetic deletion of GRIP1/2 or PICK1 eliminates cerebellar LTD.

“Consistent with this model, genetic deletion of GRIP1/2 or PICK1 eliminates cerebellar LTD (Takamiya et al., 2008, Steinberg et al., 2006).”

• cites Takamiya et al., 2008 sourceSupported
• cites Steinberg et al., 2006 sourceNot checked — no full text of the source

May combine two claims.

Cerebellar LTP does not involve trafficking of GluA3; it relies on an increase in the open-probability of GluA3-containing receptors through a cAMP-dependent pathway.

“This form of cerebellar LTP does not appear to involve trafficking of GluA3, but rather relies on an increase in the open-probability of GluA3-containing receptors through a cAMP-dependent pathway (Gutierrez-Castellanos et al., 2017).”

• cites Gutierrez-Castellanos et al., 2017 sourceSupported

May combine two claims.

Treatment with the 3Y peptide completely blocks LTD and activity-dependent GluA2 endocytosis, while having no effect on basal synaptic transmission.

“Multiple studies have shown both in slice physiology experiments and in vivo that treatment with a short peptide mimicking the tyrosine-rich region of GluA2 (called the 3Y peptide) completely blocks LTD as well as activity-dependent GluA2 endocytosis (Fox et al., 2007, Ahmadian et al., 2004), while having no effect on basal synaptic transmission.”

• cites Fox et al., 2007 sourceNot checked — no full text of the source
• cites Ahmadian et al., 2004 sourcePartly supported

  The hippocampal-slice results (Figure 7) report that GluR2 3Y significantly reduced LFS-induced LTD, while the slice recordings (Figure 6) report no effect on basal synaptic transmission. The cultured-neuron experiments (Figure 8) show blockade of insulin-stimulated AMPA receptor endocytosis, not endocytosis directly measured after activity-induced LTD. This paper therefore does not establish complete blockade of activity-dependent endocytosis or provide in vivo evidence. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

The amino terminal domain is not necessary for formation of functional ion channels, or delivery onto the cell surface, but is required for targeting and retention of GluA1 at synapses during LTP.

“Data show that the amino terminal domain is not necessary for the formation of functional ion channels, or delivery onto the cell surface, but is required for targeting and retention of GluA1 at synapses during LTP (Watson et al., 2017, Diaz-Alonso et al., 2017).”

• cites Watson et al., 2017 sourcePartly supported

  The Results section ('GluA1 requires the NTD for synaptic delivery'; page unavailable) shows that GluA1 lacking its N-terminal domain produces surface currents but fails to incorporate effectively at synapses. The LTP Results and Discussion show that potentiation cannot be maintained without the domain. However, the Discussion also reports transient potentiation and apparent synaptic incorporation of GluA1 lacking the domain, so the claim that it is required for initial targeting during LTP is too strong. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Diaz-Alonso et al., 2017 sourceNot checked — no full text of the source

May combine two claims.

Hippocampal mGluR-mediated LTD involves dephosphorylation of GluA2 Y876 and is completely blocked by inhibitors of tyrosine phosphatases.

“Interestingly, hippocampal mGluR-mediated LTD involves the dephosphorylation of GluA2 Y876 and is completely blocked by inhibitors of tyrosine phosphatases (Moult et al., 2006, Gladding et al., 2009).”

• cites Moult et al., 2006 sourcePartly supported

  The section on DHPG-LTD and AMPAR dephosphorylation (page unavailable) reports reduced tyrosine phosphorylation of GluR2 in hippocampal slices, but does not identify residue Y876. The section on PTP inhibitors (page unavailable) reports that orthovanadate and phenylarsine oxide prevented significant DHPG-LTD, supporting the inhibitor-blockade portion under the tested conditions. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Gladding et al., 2009 sourceNot checked — no full text of the source

May combine two claims.

Glutamate, AMPA, and NMDA induce GluA2 tyrosine phosphorylation, which disrupts the interaction between GluA2 and GRIP1/2 but not PICK1.

“Glutamate receptor agonists, including glutamate, AMPA and NMDA, induce GluA2 tyrosine phosphorylation which disrupts the interaction between GluA2 and GRIP1/2 but not PICK1 (Hayashi and Huganir, 2004).”

• cites Hayashi and Huganir, 2004 sourceSupported

May combine two claims.

Phosphorylation of GluA2 S880 prevents GRIP1/2 binding, promotes interaction of the GluA2 PDZ ligand with PICK1, destabilizes GluA2 within the PSD, and promotes GluA2 endocytosis.

“Phosphorylation of GluA2 S880 prevents GRIP1/2 binding and promotes the interaction of the GluA2 PDZ ligand with PICK1 (Seidenman et al., 2003, Chung et al., 2000, Steinberg et al., 2006), destabilizing GluA2 within the PSD and promoting GluA2 endocytosis.”

• cites Seidenman et al., 2003 sourceSupported
• cites Chung et al., 2000 sourcePartly supported

  The binding-results section shows that Ser880 phosphorylation prevents GluR2 (GluA2) binding to GRIP1 while preserving binding to PICK1; it does not show increased PICK1 binding or test GRIP2. The Discussion and the section on PKC-induced internalization report increased GluR2 internalization alongside Ser880 phosphorylation, but do not establish that phosphorylation itself destabilizes GluR2 within the PSD or causes endocytosis. Page numbers were not available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Steinberg et al., 2006 sourceNot checked — no full text of the source

May combine two claims.

Mice lacking PICK1, KIBRA or Grasp1 all show reductions in hippocampal LTP as well as defects in hippocampus-dependent learning and memory tasks.

“Mice lacking PICK1, KIBRA or Grasp1 all show reductions in hippocampal LTP as well as defects in hippocampus-dependent learning and memory tasks (Makuch et al., 2011, Volk et al., 2010, Chiu et al., 2017)”

• cites Makuch et al., 2011 sourceSupported
• cites Volk et al., 2010 sourcePartly supported

  The Discussion reports impaired hippocampal LTP with a pairing protocol in adult PICK1-KO mice, while other LTP protocols showed no difference. The Results report impaired inhibitory-avoidance learning in adults, but neither LTP nor learning was impaired in juvenile PICK1-KO mice. The source therefore supports the PICK1 portion of the sentence, but not its unqualified implication that these deficits occur across ages or LTP protocols; the other genes are outside this source's attribution. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Chiu et al., 2017 sourceSupported

May combine two claims.

GluA2 is ubiquitinated on K870 and K882 in response to neuronal activity, and this is dependent on AMPAR internalization.

“GluA2 is also a target of ubiquitination on K870 and K882, which occurs in response to neuronal activity and is dependent on AMPAR internalization (Widagdo et al., 2015).”

• cites Widagdo et al., 2015 sourceSupported

May combine two claims.

Phosphorylation of GluA2 S880 is required for cerebellar LTD; GluA2 K882A knock-in eliminates cerebellar LTD.

“Specifically, phosphorylation of GluA2 S880 is required as knock-in mutations that prevent phosphorylation of this site in mice (GluA2 K882A) eliminates cerebellar LTD (Chung et al., 2000, Steinberg et al., 2006).”

• cites Chung et al., 2000 sourcePartly supported

  The ‘PKC phosphorylates serine-880 of GluR2’ section establishes phosphorylation at this site, and the Discussion suggests it may regulate AMPA-receptor internalization during synaptic plasticity. The paper does not establish that S880 phosphorylation is required for cerebellar LTD or report that a K882A knock-in eliminates it. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Steinberg et al., 2006 sourceNot checked — no full text of the source

May combine two claims.

Scaling-up can be rescued by expression of shRNA-resistant WT GluA2, but not by a GluA2 chimera with the C-tail swapped for GluA1, suggesting that elements of the GluA2 C-terminus are required for scaling-up.

“Scaling-up can be rescued by expression of shRNA-resistant WT GluA2, but not by a GluA2 chimera with the C-tail swapped for GluA1, suggesting that elements of the GluA2 C-terminus are required for scaling-up (Gainey et al., 2009).”

• cites Gainey et al., 2009 sourceSupported

May combine two claims.

GluA1 S567 is phosphorylated by CaMKII and promotes removal of GluA1 from synapses.

“A phosphorylation site was identified in the first intracellular loop of GluA1 (S567) which is phosphorylated by CaMKII and promotes removal of GluA1 from synapses (Lu et al., 2010, Coultrap et al., 2014).”

• cites Lu et al., 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Coultrap et al., 2014 sourceSupported

May combine two claims.

Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons.

“Scaling-up involves an increase in phosphorylation of GluA1 S845, but not S831, and is completely blocked in neurons with GluA1 S845A knock-in mutations, but remains intact in GluA1 S831A mutant neurons (Diering et al., 2014, Kim and Ziff, 2014).”

• cites Diering et al., 2014 sourceSupported
• cites Kim and Ziff, 2014 sourcePartly supported

  The Results section, “pGluA1(S845) Is Required for TTX-Induced Synaptic Scaling” (page unavailable), reports increased S845 phosphorylation after TTX treatment and says TTX could not induce scaling in neurons from GluA1 S845A knock-in mice. Our copy does not address whether S831 phosphorylation increases or whether scaling remains intact in S831A mutant neurons (searched: S831 phosphorylation, S831A mutant neurons). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Bicuculline treatment stimulates GluA2 ubiquitination on K882, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down.

“Bicuculline treatment stimulates GluA2 ubiquitination on K882 (Widagdo et al., 2015), very close to the Y876 and S880 phosphorylation sites, and AMPAR ubiquitination has been shown to be required for homeostatic scaling-down (Scudder et al., 2014).”

• cites Widagdo et al., 2015 sourcePartly supported

  The Results section reports that bicuculline induces ubiquitination of GluA2, and a separate Results section identifies K882 as a major GluA2 ubiquitination site. However, the K882 mapping used AMPA treatment, not bicuculline, so the paper does not establish that bicuculline stimulates ubiquitination specifically at K882. The scaling-down statement is cited to Scudder et al., not to Widagdo et al. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Scudder et al., 2014 sourcePartly supported

  In the section on homeostatic downscaling (pages not supplied), the paper reports increased AMPAR ubiquitination after bicuculline treatment and shows that Nedd4-1 knockdown prevents downscaling of surface AMPARs and synaptic strength. It establishes that Nedd4-1 is required, but does not directly show that ubiquitination of AMPARs themselves is required. The GluA2 K882 claim is attributed to a different citation and is not part of this verdict. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

During LTD, GluA1 T840 is dephosphorylated by PP1/PP2A and S845 by CaN.

“GluA1 undergoes dephosphorylation of T840 and S845 during LTD by protein phosphatases PP1/PP2A and CaN, respectively (Delgado et al., 2007, Toda and Huganir, 2015, Lee et al., 1998, Sanderson et al., 2016).”

• cites Delgado et al., 2007 sourcePartly supported

  The Results sections on chem-LTD and T840 phosphatases report persistent T840 dephosphorylation during chemical LTD and show that inhibiting PP1/PP2A prevents NMDA-induced T840 dephosphorylation. They do not establish the same change during synaptically induced LTD, and the paper does not identify CaN as the phosphatase responsible for S845 dephosphorylation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Toda and Huganir, 2015 sourcePartly supported

  The Abstract links S845 phosphorylation changes to LTD, and the Results report that a PP1/PP2A inhibitor blocks T840 dephosphorylation after PACAP38 stimulation. The paper does not establish that PP1/PP2A dephosphorylates T840 during LTD or that CaN dephosphorylates S845 during LTD; the Discussion describes PACAP38’s possible role in LTD as conceivable and requiring further study (page numbers unavailable). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Lee et al., 1998 sourceNot checked — no full text of the source

May combine two claims.

Neither GRIP1/2 nor PICK1 are required for scaling-down.

“Neither GRIP1/2 nor PICK1 are required for scaling-down (Tan et al., 2015, Anggono et al., 2011).”

• cites Tan et al., 2015 sourceSupported
• cites Anggono et al., 2011 sourcePartly supported

  The Results report robust scaling-down after bicuculline treatment in PICK1 knockout neurons, supporting the PICK1 part of the sentence. The cited paper does not establish that GRIP1/2 are dispensable for scaling-down, so it does not support the full claim attributed jointly to the two citations. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Scaling-up appears to involve increased tyrosine phosphorylation of GluA2 as a result of downregulation of the tyrosine phosphatase STEP61, and scaling-up could be blocked by exogenously applied STEP61.

“Scaling-up appears to involve increased tyrosine phosphorylation of GluA2 as a result of downregulation of the tyrosine phosphatase, STEP61 (Figure 3), and scaling-up could be blocked by exogenously applied STEP61 (Jang et al., 2015).”

• cites Jang et al., 2015 sourcePartly supported

  The Results and discussion report that activity blockade reduced STEP61 and increased GluA2 tyrosine phosphorylation, and that TAT-STEP WT preincubation abolished TTX-induced synaptic scaling. However, the applied TAT-STEP protein was a STEP46 fusion, not exogenously applied STEP61 as the claim specifies. Page numbers were not provided in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Complete knock-out of GluA1 still allowed for the scaling-up of GluA2/3, and complete knock-out of GluA2/3 still allowed for the scaling-up of GluA1.

“Despite the fact that both GluA1 and GluA2 have been implicated in homeostatic scaling-up, complete knock-out of GluA1 still allowed for the scaling-up of GluA2/3, and complete knock-out of GluA2/3 still allowed for the scaling-up of GluA1 (Altimimi and Stellwagen, 2013), suggesting that regulatory elements in GluA1/2 can be circumvented by complete removal of these subunits.”

• cites Altimimi and Stellwagen, 2013 sourceSupported

May combine two claims.

During scaling-down, GRIP1 protein is upregulated but remains in intracellular compartments where it may act to sequester internalized GluA2-containing receptors away from the synapse.

“Concomitantly, GRIP1 protein is upregulated during scaling-down, but remains in intracellular compartments where it may act to sequester internalized GluA2-containing receptors away from the synapse (Figure 3) (Tan et al., 2015).”

• cites Tan et al., 2015 sourcePartly supported

  The section on GRIP1 subcellular distribution (Fig. 4) reports that scaling down increases cytoplasmic GRIP1 and decreases synaptic GRIP1. It describes a cytoplasmic GRIP1 pool that can retain AMPARs intracellularly, but does not show that the increased pool sequesters internalized GluA2-containing receptors during scaling down; it instead reports reduced overall GRIP1–GluA2 interaction. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Scaling-up can be blocked by expression of the soluble cytosolic C-terminal tail of GluA2 or by shRNA-mediated knock-down of GluA2.

“Scaling-up can be blocked by the expression of the soluble cytosolic C-terminal tail of GluA2 or by shRNA-mediated knock-down of GluA2 (Gainey et al., 2009, Ancona Esselmann et al., 2017).”

• cites Gainey et al., 2009 sourceSupported
• cites Ancona Esselmann et al., 2017 sourceNot checked — no full text of the source

May combine two claims.

GluA1 T840 phosphorylation increases GluA1 single channel conductance, while phosphorylation of S845 increases channel open probability.

“GluA1 T840 phosphorylation has been shown to increase GluA1 single channel conductance while phosphorylation of S845 increases channel open probability, suggesting that dephosphorylation of these sites might also be important to reduce ion channel properties for expression of LTD (Banke et al., 2000, Jenkins et al., 2014).”

• cites Banke et al., 2000 sourcePartly supported

  The Discussion states that phosphorylation of GluR1 Ser845 increases peak open probability, supporting the S845 part of the claim. The paper does not address T840 phosphorylation or attribute increased single-channel conductance to T840; its Discussion instead associates increased unitary conductance with Ser831 phosphorylation. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Jenkins et al., 2014 sourceSupported

May combine two claims.

During the induction phase of LTD, transient signaling from synaptic CP-AMPARs is required for the full expression of LTD, and these CP-AMPARs signal their own removal through activation of calcineurin.

“During the induction phase of LTD, transient signaling from synaptic CP-AMPARs is required for the full expression of LTD, and during the progression of LTD induction these CP-AMPARs signal their own removal through activation of calcineurin (CaN) (Sanderson et al., 2016).”

• cites Sanderson et al., 2016 sourceSupported

May combine two claims.

CaMKII activity is required during LTD, where a prolonged weak stimulus favors phosphorylation of GluA1 S567 over S831, leading to removal of synaptic GluA1.

“CaMKII is well known to be required for LTP, but its activity is also required during LTD where a prolonged “weak” stimulus favors the phosphorylation of GluA1 S567 over S831, leading to removal of synaptic GluA1 (Coultrap et al., 2014).”

• cites Coultrap et al., 2014 sourceSupported

May combine two claims.

Prolonged TTX treatment in cultured neurons causes lysosomal degradation of PICK1, while deletion of PICK1 enhances mEPSC amplitude and occludes homeostatic scaling-up.

“Prolonged TTX treatment in cultured neurons causes lysosomal degradation of PICK1, while deletion of PICK1 enhances mEPSC amplitude and occludes homeostatic scaling-up, suggesting that decreased activity of PICK1 is an important mediator of scaling-up (Figure 3) (Anggono et al., 2011).”

• cites Anggono et al., 2011 sourceSupported

May combine two claims.

Visual deprivation-induced scaling-up in mouse visual cortex involves the recruitment of synaptic CP-AMPARs and increased GluA1 S845 phosphorylation.

“Homeostatic scaling-up has also been observed in the visual cortex in mice in response to visual deprivation, and involves the recruitment of synaptic CP-AMPARs and increased GluA1 S845 phosphorylation (Goel et al., 2006, Goel et al., 2011).”

• cites Goel et al., 2006 sourceNot checked — no full text of the source
• cites Goel et al., 2011 sourceSupported

May combine two claims.

TTX-induced homeostatic scaling-up in cultured neurons increases GluA1 protein expression as well as surface and synaptic levels of CP-AMPARs (GluA1 homomers) and GluA1/2 heteromers, but not GluA3-containing AMPARs.

“TTX-induced homeostatic scaling-up in cultured neurons increases GluA1 protein expression as well as surface and synaptic levels of CP-AMPARs (GluA1 homomers) and GluA1/2 heteromers but not in GluA3-containing AMPARs (Figure 3) (Diering et al., 2014, Soares et al., 2013, Tan et al., 2015, Kim and Ziff, 2014, Hu et al., 2010).”

• cites Diering et al., 2014 sourcePartly supported

  The Results section, “Changes in AMPAR phosphorylation during homeostatic scaling” (page unavailable), reports that 48 hours of TTX increased surface GluA1 and GluA2 but not GluA3, consistent with GluA1/2-containing receptors rather than GluA2/3-containing receptors. Other Results passages report synaptic recruitment of GluA1 and changes in total AMPAR expression, but do not establish increased total GluA1 specifically or increased surface and synaptic levels of both GluA1 homomers (CP-AMPARs) and GluA1/2 heteromers. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Soares et al., 2013 sourcePartly supported

  In “Homeostatic upregulation of synaptic GluA2-lacking AMPARs” (page unavailable), the paper reports increased total and surface GluA1 after TTX treatment and evidence of synaptic GluA2-lacking AMPARs in organotypic hippocampal slices. It does not establish that these receptors are specifically GluA1 homomers, that GluA1/2 heteromers increase, or that GluA3-containing AMPARs do not increase. The claim also describes cultured neurons more broadly than the slice preparation studied. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Tan et al., 2015 sourcePartly supported

  The Results section reports that chronic TTX increased total GluA1 and surface GluA1 and GluA2, but not surface GluA3. The Discussion interprets the surface changes as preferential GluA1/GluA2 heteromer insertion. It does not establish increased surface or synaptic GluA1-homomer CP-AMPARs; instead, it says their synaptic insertion was unlikely to predominate (page numbers unavailable). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Dephosphorylation of GluA2 S880 during scaling-down is mediated by activation of phosphatase PP1 through its regulatory protein inhibitor 2 (I-2), while dephosphorylation of GluA2 Y876 requires an upregulation of STEP61.

“Dephosphorylation of GluA2 S880 during scaling-down is mediated by activation of phosphatase PP1, through its regulatory protein inhibitor 2 (I-2) (Siddoway et al., 2013), while dephosphorylation of GluA2 Y876 requires an upregulation of STEP61 (Jang et al., 2015).”

• cites Siddoway et al., 2013 sourceSupported
• cites Jang et al., 2015 sourcePartly supported

  The Jang citation attaches to the STEP61/GluA2 Y876 clause, not the PP1/I-2 clause. In Results and discussion (page not supplied), increased STEP61 coincided with reduced phosphorylation of GluA2 at a three-tyrosine site that includes Y876. The authors say the specific GluA2 tyrosine residues regulated by STEP61 are unknown, and inhibiting STEP did not block the measured reduction in three-tyrosine phosphorylation; the paper therefore does not establish that Y876 dephosphorylation requires STEP61 upregulation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Bicuculline-induced scaling-down in cultured neurons involves the downregulation of GluA1/2/3 protein levels as well as a reduced synaptic targeting of all AMPAR subunits.

“Bicuculline-induced scaling-down in cultured neurons involves the downregulation of GluA1/2/3 protein levels as well a reduced synaptic targeting of all AMPAR subunits (Diering et al., 2014, Tan et al., 2015).”

• cites Diering et al., 2014 sourcePartly supported

  The Results section, “Changes in AMPAR phosphorylation during homeostatic scaling” (page unavailable), reports that bicuculline reduced cell-surface GluA1, GluA2 and GluA3 in cultured neurons. “GluA1 phospho-S845 is required for scaling-up” mentions changes in total AMPAR expression but does not specify downregulation of all three subunits. The copy documents reduced PSD-associated GluA1, not reduced synaptic targeting of every subunit. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Tan et al., 2015 sourcePartly supported

  The ‘Inactivity-Induced Synaptic Scaling Is Blocked in GRIP Knockout’ section reports that bicuculline reduced total GluA1, GluA2, and GluA3 expression and reduced surface levels of all three in cultured neurons (Fig. S1; Fig. 3 A–D). It does not establish reduced synaptic targeting of each subunit specifically; the reported subunit-specific measurements are of surface levels. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

AMPARs play an essential role in the functioning of the brain, and changes in the abundance of post-synaptic AMPARs are a fundamental mechanism for most forms of synaptic plasticity.

“AMPARs play an essential role in the functioning of the brain, and changes in the abundance of post-synaptic AMPARs are a fundamental mechanism for most forms of synaptic plasticity (Huganir and Nicoll, 2013).”

• cites Huganir and Nicoll, 2013 sourcePartly supported

  The Conclusions and Future Directions section says changes in AMPAR number at synaptic spines mediate changes in strength during LTP and LTD. The Proposed Working Models for LTP section calls AMPAR regulation key to many forms of synaptic plasticity and important for learning and memory, but it does not establish the claim’s stronger scope of “most forms.” Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

The 'slot hypothesis' offers some explanation for the prominent role of GluA1 in LTP and of GluA2 in LTD, via the rapid activity-dependent mobilization of GluA1-containing receptors onto the cell surface during LTP, and the removal of GluA2 containing receptors from the cell-surface during LTD through interactions with AP2 and/or through interactions involving the GluA2 Y-rich motif.

“Thus the “slot hypothesis” offers some explanation for the prominent role of GluA1 in LTP and of GluA2 in LTD, via the rapid activity-dependent mobilization of GluA1-containing receptors onto the cell surface during LTP, and the removal of GluA2 containing receptors from the cell-surface during LTD through interactions with AP2 and/or through interactions involving the GluA2 Y-rich motif (Ahmadian”

• cites Ahmadian et al., 2004 sourceSupported
• cites Anggono and Huganir, 2012 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Huganir and Nicoll, 2013 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Synaptic GluA1 is dephosphorylated at S831 and S845 during scaling-down and also in the forebrain during sleep.

“Synaptic GluA1 is dephosphorylated at S831 and S845 during scaling-down and also in the forebrain during sleep (Diering et al., 2014, Diering et al., 2017), which together with other observations suggests that homeostatic scaling-down occurs across the forebrain during sleep (Diering et al., 2017).”

• cites Diering et al., 2014 sourcePartly supported

  The Results section, “Changes in AMPAR phosphorylation during homeostatic scaling” (page unavailable), reports decreased GluA1 phosphorylation at both S831 and S845 after bicuculline-induced scaling-down. It does not establish that both decreases occurred specifically in synaptic GluA1. The sleep finding is separately attributed to Diering et al. (2017), not to this source. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Diering et al., 2017 sourceSupported

May combine two claims.

Forms of LTP, LTD and homeostatic scaling have been shown to be intact in knock-out mice of different AMPAR subunits as well as in molecular replacement experiments.

“Forms of LTP, LTD and homeostatic scaling have been shown to be intact in knock-out mice of different AMPAR subunits as well as in using molecular replacement experiments (Huganir and Nicoll, 2013, Granger et al., 2013, Ancona Esselmann et al., 2017).”

• cites Huganir and Nicoll, 2013 sourcePartly supported

  In “Subunit Dependence of AMPAR Trafficking and LTP and LTD” (page unavailable), the review reports that molecular replacement found no specific AMPAR-subunit requirement for LTP. “NMDAR-Dependent LTD” reports normal LTD in mice lacking GluA2/GluA3 or GluA1. The review describes homeostatic synaptic scaling in “Dynamic Regulation of AMPAR Membrane Trafficking,” but does not say it remains intact in AMPAR-subunit knockout mice or molecular replacement experiments. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Granger et al., 2013 sourcePartly supported

  The Introduction and the section “LTP requires a reserve pool of AMPARs” report normal LTP with some molecular replacements and with GluA2 or GluA3 deletion. But the latter section reports impaired LTP after GluA1 deletion, so the knockout claim is too broad. The paper does not establish intact LTD or homeostatic scaling in these experiments. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites Ancona Esselmann et al., 2017 sourceNot checked — no full text of the source

May combine two claims.

GluA2-containing receptors (likely GluA2/3 heteromers) undergo spontaneous and constitutive exocytosis, but these events are much smaller, containing an estimated 2-5 receptors.

“GluA2-containing receptors (likely GluA2/3 heteromers) undergo spontaneous and constitutive exocytosis, but these events are much smaller, containing an estimated 2-5 receptors (Araki et al., 2010, Gu et al., 2016, Lin et al., 2009).”

• cites Araki et al., 2010 sourcePartly supported

  The Discussion reports that GluA2 exocytosis is largely constitutive (approximately 70%) and that its insertion events contain only a few receptors compared with GluA1; it also discusses GluA2/3 heteromers. The Results report lower fluorescence intensity for GluA2 events, but our copy does not give the claimed estimate of 2–5 receptors per event. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Gu et al., 2016Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Lin et al., 2009 sourcePartly supported

  In Results, under “Capturing insertion events of GluRs” (page unavailable), the paper associates GluR2 with constitutive trafficking but says it rarely observed GluR2 insertion under normal conditions. It does not identify those receptors as likely GluR2/3 heteromers or support the estimate of 2–5 receptors per event. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

GluA1 which remains phosphorylated is resistant to scaling-down, and the unphosphorylated GluA1-containing receptors are preferentially removed.

“Interestingly, GluA1 which remains phosphorylated is resistant to scaling-down and the unphosphorylated GluA1 containing receptors are preferentially removed (Figure 4) (Diering et al., 2014).”

• cites Diering et al., 2014 sourceSupported

May combine two claims.

GluA2 can directly interact with AP-2 clathrin adapter complex, which allows GluA2-containing receptors to be rapidly depleted from the cell-surface.

“GluA2 can directly interact with AP-2 clathrin adapter complex, which allows GluA2-containing receptors to be rapidly depleted from the cell-surface (Kastning et al., 2007, Lee et al., 2002).”

• cites Kastning et al., 2007 sourceSupported
• cites Lee et al., 2002 sourceNot checked — no full text of the source

May combine two claims.

Four subunits GluA1-4 assemble into tetramers to make the core functional ion channel, with different combinations conferring unique cellular trafficking behaviors and biophysical characteristics.

“Four subunits, GluA1-4, assemble into tetramers to make up the core functional ion channel, with different combinations conferring unique cellular trafficking behaviors and biophysical characteristics (Shepherd and Huganir, 2007).”

• cites Shepherd and Huganir, 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S4 (based).

Layers of regulation through interactions and modifications increase the computational power of synapses.

“Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses.”

May combine two claims.

In some cases, certain AMPAR PTMs can influence others, either by inhibiting or promoting neighboring modification, suggesting that of all possible AMPAR variants some will be favored.

“In some cases, it has been shown that certain AMPAR PTMs can influence others (Figure 1C), either by inhibiting or promoting the neighboring modification, suggesting that of all possible AMPARs variants some will be favored.”

May combine two claims.

AMPAR subunits contain highly conserved ligand binding and transmembrane domains that allow glutamate binding and channel pore assembly, but are divergent in extracellular amino-terminal domains and cytoplasmic carboxy-terminal tails which are subject to PTMs.

“AMPAR subunits contain highly conserved ligand binding and transmembrane domains that allow glutamate binding and channel pore assembly respectively, but are divergent in their extracellular amino-terminal domains and cytoplasmic carboxy-terminal tails which are subject to PTMs (Shepherd and Huganir, 2007) (Figure 1).”

• cites Shepherd and Huganir, 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Long-tailed AMPARs are recruited to synapses in an activity-dependent manner, while short-tailed AMPARs undergo constitutive cycling in and out of synapses.

“Earlier studies suggest that long-tailed AMPARs are recruited to synapses in an activity-dependent manner, while short-tailed AMPARs undergo constitutive cycling in and out of synapses (Shi et al., 2001, Hayashi et al., 2000).”

• cites Shi et al., 2001 sourceNot checked — no full text of the source
• cites Hayashi et al., 2000 sourceNot checked — no full text of the source

May combine two claims.

The dynamic nature of AMPARs suggests that the AMPAR code will function by shifting equilibriums in favor of synaptic accumulation or removal, and by altering ion channel properties.

“The dynamic nature of AMPARs suggests that the AMPAR code will function by shifting equilibriums in favor of synaptic accumulation or removal, and by altering ion channel properties.”

May combine two claims.

The GluA1 C-terminal tail is both necessary and sufficient for hippocampal LTP.

“recent data from Zhou et al., provide strong evidence that the GluA1 C-terminal tail is both necessary and sufficient for hippocampal LTP (Zhou et al., 2017).”

• cites Zhou et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

GluA2-containing receptors have a linear current-voltage relationship and are impermeable to Ca2+, while GluA2-lacking receptors show high conductance, rapid decay kinetics, inward-rectification due to voltage-dependent block by intracellular polyamines, and are permeable to Ca2+.

“The result of this modification is that GluA2 containing receptors have a linear current-voltage (I-V) relationship and are impermeable to Ca2+, while GluA2-lacking receptors show high conductance and rapid decay kinetics, inward-rectification due to voltage-dependent block by intracellular polyamines and are permeable to Ca2+, thus GluA2-lacking receptors are usually referred to as calcium-perme”

• cites Burnashev et al., 1992 sourceNot checked — no full text of the source

May combine two claims.

For each type of plasticity, certain AMPAR variants will be preferentially added or removed from synapses or undergo selective changes in channel properties.

“For each type of plasticity, certain AMPAR variants will be preferentially added or removed from synapses or undergo selective changes in channel properties.”

May combine two claims.

LTP was rescued in GluA1C2KI and GluA2C1KI double mutant mice, showing that the C-tail of GluA1 is sufficient for LTP expression, even when attached to the GluA2 subunit.

“Incredibly, LTP was rescued in GluA1C2KI and GluA2C1KI double mutant mice, showing that the C-tail of GluA1 is sufficient for LTP expression, even when it is attached to the GluA2 subunit (Zhou et al., 2017).”

• cites Zhou et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

GluA1 undergoes 11 known PTMs each of which can occur independently and reversibly, allowing for 2^11, or 2,048 possible modified variants of GluA1.

“As an example, GluA1 undergoes 11 known PTMs each of which can occur independently and reversibly (7 phosphorylations, 2 palmitoylations, 1 S-nitrosylation, 1 ubiquitination), allowing for 211, or 2,048 possible modified variants of GluA1”

May combine two claims.

While phosphorylation of GluA1 S831 or S845 are clearly involved in LTP, the strict requirement for each site as well as the synergistic effects of dual phosphorylation are likely synapse- and induction-specific.

“Thus, while phosphorylation of GluA1 S831 or S845 are clearly involved in LTP, the strict requirement for each site as well as the synergistic effects of dual phosphorylation are likely synapse- and induction-specific.”

May combine two claims.

LTP was completely absent in GluA1C2KI mice, demonstrating that the GluA1 C-tail is necessary for LTP.

“Importantly, LTP was completely absent in GluA1C2KI mice, demonstrating that the GluA1 C-tail is necessary for LTP.”

• cites Zhou et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

All four AMPAR subunits are palmitoylated at a conserved cysteine residue in the C-terminal juxtamembrane region and a second site within transmembrane domain TM2.

“All four AMPAR subunits are palmitoylated at a conserved cysteine residue in the C-terminal juxtamembrane region (GluA1 C811, GluA2 C836, GluA3 C841, GluA4 C817) and a second site within the transmembrane domain TM2 (Hayashi et al., 2005).”

• cites Hayashi et al., 2005 sourceNot checked — no full text of the source

May combine two claims.

Synaptic potentiation through GluA3 may not require AMPAR trafficking, but rather cAMP-dependent enhancement of channel open-probability of GluA3-containing receptors already localized to synapses, allowing for very rapid changes in synaptic efficacy.

“Therefore, synaptic potentiation through GluA3 may not require AMPAR trafficking, but rather cAMP-dependent enhancement of channel open-probability of GluA3-containing receptors already localized to synapses, allowing for very rapid changes in synaptic efficacy.”

May combine two claims.

The mechanism of S880 regulation likely also applies to GluA3, which interacts with GRIP1/2 and PICK and has a conserved phosphorylation site S885.

“This mechanism likely also applies to GluA3, which also interacts with GRIP1/2 and PICK and the phosphorylation site, S885 is conserved with GluA2 S880 (Figure 1B).”

May combine two claims.

During LTD, AMPARs are removed from the PSD via lateral diffusion and locally depleted from the cell surface by clathrin- and dynamin-dependent endocytosis.

“AMPARs must be removed from the PSD, allowing for lateral diffusion away from the synapse, and concomitantly, AMPARs are locally depleted from the cell-surface by clathrin- and dynamin-dependent endocytosis (Shepherd and Huganir, 2007).”

• cites Shepherd and Huganir, 2007 sourceNot checked — no full text of the source

May combine two claims.

If PKA is not able to phosphorylate GluA1 S845, CP-AMPAR recruitment to synapses during LTD is blocked, possibly explaining the complete absence of LTD in GluA1 S845A knock-in mice.

“If PKA is not able to phosphorylate GluA1 S845, CP-AMPAR recruitment to synapses during LTD is blocked, possibly explaining the complete absence of LTD in GluA1 S845A knock-in mice.”

May combine two claims.

Hippocampal LTD is still observed in knock-outs of GluA2/3, but not in neurons expressing GluA2 fused to the GluA1 C-tail.

“Hippocampal LTD is still observed in knock-outs of GluA2/3 (Meng et al., 2003), but not in neurons expressing GluA2 fused to the GluA1 C-tail (Zhou et al., 2017).”

• cites Meng et al., 2003 sourceNot checked — no full text of the source
• cites Zhou et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

GluA1 S845 dephosphorylation is critical for hippocampal LTD, as the GluA1 S845A mutation results in impaired LTD.

“GluA1 S845 dephosphorylation is critical for hippocampal LTD, as the GluA1 S845A mutation results in impaired LTD (Lee et al., 2003, Lee et al., 2010), indicating that the induction of LTD requires PKA phosphorylation of GluA1 even though receptors are eventually dephosphorylated (Huganir and Nicoll, 2013).”

• cites Lee et al., 2003 sourceNot checked — no full text of the source
• cites Lee et al., 2010 sourceNot checked — no full text of the source

May combine two claims.

Synaptic plasticity is modulated by regulatory elements within the AMPAR C-tails, but this regulation is circumvented in the absence of AMPAR subunits.

“Again, these findings suggest that synaptic plasticity is modulated by regulatory elements with the AMPAR C-tails, but this regulation is circumvented in the absence of AMPAR subunits.”

May combine two claims.

The GluA2 C-tail is both necessary and sufficient for hippocampal NMDAR-LTD.

“NMDAR-LTD can be rescued in the GluA1C2KI/GluA2C1KI double mutants, showing that the GluA2 C-tail is both necessary and sufficient for hippocampal NMDAR-LTD.”

• cites Zhou et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

During synaptic plasticity, the number of PSD slots may be altered, and/or the affinity of PSD slots for AMPARs might be changed, such that AMPARs can accumulate in the PSD during LTP and are removed during LTD.

“During synaptic plasticity, the number of PSD slots may be altered, and/or the affinity of PSD slots for AMPARs might be changed, such that AMPARs can accumulate in the PSD during LTP and are removed during LTD (Figure 2).”

May combine two claims.

In the plane of the plasma membrane, AMPARs are highly mobile but become trapped in PSD slots.

“In the plane of the plasma membrane, AMPARs are highly mobile but become trapped in PSD slots (Opazo et al., 2012).”

• cites Opazo et al., 2012 sourceNot checked — no full text of the source