AKAP150-Anchored Calcineurin Regulates Synaptic Plasticity by Limiting Synaptic Incorporation of Ca2+-Permeable AMPA Receptors

Classified as probably not a substantial claim. May combine two claims.

Phosphorylation of AMPAR GluA1 subunits on S845 by PKA increases channel open probability and promotes receptor recycling and exocytosis at extrasynaptic sites near the postsynaptic density.

“Phosphorylation of AMPAR GluA1 (formerly GluR1) subunits on S845 by PKA increases channel open probability and promotes receptor recycling and exocytosis at extrasynaptic sites near the postsynaptic density (PSD)”

• cites Banke et al., 2000 sourcePartly supported

  The Discussion reports that PKA phosphorylation of GluR1 Ser845 appears to increase peak channel open probability. The paper does not establish the additional claim that this phosphorylation promotes receptor recycling or exocytosis at extrasynaptic sites near the PSD; the passages on receptor localization discuss it only as background. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Ehlers, 2000 sourceNot checked — no full text of the source
• cites Esteban et al., 2003 sourceNot checked — no full text of the source

May combine two claims.

In cultured rat hippocampal neurons, Ca2+, CaN activity, and the AKAP79/150 CaN anchoring domain are required for down-regulation of AMPAR currents and internalization of AMPAR in response to acute NMDA receptor activation or inhibition of PKA anchoring and activity.

“In cultured rat hippocampal neurons, Ca2+, CaN activity, and the AKAP79/150 CaN anchoring domain are required for the down-regulation of AMPAR currents and internalization of AMPAR in response to either acute NMDA receptor activation or inhibition of PKA anchoring and activity”

• cites Beattie et al., 2000 sourceNot checked — no full text of the source
• cites Tavalin et al., 2002 sourcePartly supported

  The Results section reports that disrupting PKA anchoring reduced AMPA receptor currents in cultured hippocampal neurons, and that removing extracellular calcium or inhibiting PP2B prevented this rundown. It does not establish that the AKAP79/150 PP2B-anchoring domain is required in those neurons, or show AMPA receptor internalization. NMDA receptors were blocked during the current recordings, rather than acutely activated. Page numbers are unavailable in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Hoshi et al., 2005 sourcePartly supported

  The Results report that, in cultured rat hippocampal neurons, AKAP150 silencing abolished glutamate-dependent attenuation of AMPA currents and that rescue required the PP2B (calcineurin) anchoring site. They also report that inhibiting PKA activity with PKI induced AMPA-current downregulation. The passages do not establish a requirement for Ca2+ or calcineurin activity, or show AMPAR internalization or a response specifically to acute NMDA receptor activation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Hippocampal slices from AKAP150 knockout mice exhibit normal LTD and LTP under the same conditions where AKAP150D36 mice show strong deficits in both LTP and LTD, suggesting that simultaneous removal of both PKA and CaN anchoring allows compensation.

“hippocampal slices from AKAP150 knockout mice exhibit normal LTD and LTP under the same conditions where AKAP150D36 mice show strong deficits in both LTP and LTD, suggesting that simultaneous removal of both PKA and CaN anchoring allows compensation”

• cites Weisenhaus et al., 2010 sourceSupported

May combine two claims.

LTD-associated loss of AKAP-PKA complexes from spines and the PSD is coincident with, but slightly delayed from, GluA1 S845 dephosphorylation and endocytosis, and may prevent re-phosphorylation of GluA1.

“LTD-associated loss of AKAP-PKA complexes from spines and the PSD is coincident with, but slightly delayed in time from GluA1 S845 dephosphorylation and endocytosis, and may prevent re-phosphorylation of GluA1”

• cites Smith et al., 2006 sourceSupported

May combine two claims.

In ~2-3 week-old mice, where synaptic plasticity is normal in AKAP150 knockouts, characterization of AKAP150ΔPIX mice revealed that CaN anchoring is essential for LTD and constrains LTP.

“in ~2–3 week-old mice, where synaptic plasticity is normal in AKAP150 knockouts (Weisenhaus et al., 2010), our characterization of AKAP150ΔPIX mice revealed that CaN anchoring is essential for LTD and constrains LTP”

• cites Weisenhaus et al., 2010 sourcePartly supported

  The citation supports the knockout comparison, not the citing authors’ subsequent finding about AKAP150ΔPIX mice. The Results and Figure 5 report normal LTD in AKAP5 knockout mice at 10–14 days, but normal LTP was measured in 7–12-week-old mice; the paper does not establish that both forms of plasticity are normal at ~2–3 weeks (no page numbers provided). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

CaN is anchored within 10 nm of PKA on the AKAP, likely allowing this kinase-phosphatase pair to precisely balance each other in regulation of substrates such as GluA1 S845.

“CaN is anchored within 10 nm of PKA on the AKAP (Oliveria et al., 2003), likely allowing this kinase-phosphatase pair to precisely balance each other in regulation of substrates such as GluA1 S845.”

• cites Oliveria et al., 2003 sourceSupported

May combine two claims.

LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses.

“LTD leads to loss of AKAP79/150 binding to PSD-95 and cadherins and removal of the AKAP and PKA from synapses”

• cites Gomez et al., 2002 sourcePartly supported

  The section on AKAP79/150–PKA association with PSD-MAGUKs reports that NMDA treatment disrupts those complexes, while the section on pathways shared with LTD describes NMDA-triggered removal of the AKAP79/150–PKA complex from synapses. The paper connects these findings to LTD-related signaling, but does not show that LTD itself causes them; the passages do not establish loss of binding to cadherins. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Gorski et al., 2005 sourceNot checked — no full text of the source
• cites Smith et al., 2006 sourcePartly supported

  The Results section on PKA redistribution reports that chem-LTD treatment reduces AKAP150 and PKA at the postsynaptic density. The Introduction says disruption of AKAP79/150 binding to PSD-95 and cadherins was observed after stronger NMDA treatments than those needed to induce LTD; this paper does not establish that the binding loss occurs under its LTD-inducing conditions. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

AKAP79/150 is targeted to dendritic spines and the PSD by an N-terminal basic region that is palmitoylated on two Cys residues and binds directly to PIP2, the actin cytoskeleton, and cadherin adhesion molecules.

“AKAP79/150 is targeted to dendritic spines and the PSD by an N-terminal basic region that is palmitoylated on two Cys residues and binds directly to the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), the actin cytoskeleton, and cadherin adhesion molecules”

• cites Dell'Acqua et al., 1998Not matched

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

• cites Gomez et al., 2002 sourcePartly supported

  The Results section reports that the AKAP79 N-terminal basic domain targets dendritic spines and binds F-actin; it also identifies PI-4,5-P2-binding basic regions. The same section attributes palmitoylation sites to PSD-95, not AKAP79, and the passages do not support binding to cadherin adhesion molecules. No page numbers are available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Gorski et al., 2005 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

AKAP79/150 palmitoylation targets it to dendritic recycling endosomes in cultured neurons to specifically control GluA1 trafficking and Ca2+-permeable AMPAR synaptic activity.

“our recent published findings indicated that AKAP79/150 palmitoylation targets it to dendritic recycling endosomes in cultured neurons to specifically control GluA1 trafficking and Ca2+-permeable AMPAR synaptic activity”

• cites Keith et al., 2012 sourceSupported

May combine two claims.

GluA1 phosphorylation directly regulates trafficking, but there are other phosphatase substrates, including PSD-95 and Stargazin, that are also involved in synaptic AMPAR removal during LTD.

“GluA1 phosphorylation directly regulates trafficking, but there are other phosphatase substrates, including PSD-95 and Stargazin, that are also involved in synaptic AMPAR removal during LTD.”

• cites Colledge et al., 2003 sourcePartly supported

  The Discussion and the section on PSD-95 ubiquitination link PSD-95 to NMDA-induced AMPA receptor removal, and the paper reports that proteasome inhibitors block LTD (page numbers unavailable). It suggests PP2B may participate in PSD-95 degradation, but does not establish PSD-95 as a direct phosphatase substrate; the Introduction mentions stargazin in AMPA receptor targeting, not as a phosphatase substrate involved in receptor removal during LTD. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Tomita et al., 2005 sourceNot checked — no full text of the source
• cites Kim et al., 2007 sourceNot checked — no full text of the source

May combine two claims.

LTD and depotentiation are sensitive to genetic manipulations of CaN and PKA expression, but their underlying signaling mechanisms are distinct.

“While LTD and depotentiation are sensitive to genetic manipulations of CaN and PKA expression, their underlying signaling mechanisms are distinct”

• cites Brandon et al., 1995 sourcePartly supported

  The Abstract reports that mice lacking the PKA RIβ subunit have severe deficits in both LTD and depotentiation, supporting sensitivity to a genetic manipulation of PKA. Our copy does not report a genetic manipulation of calcineurin (CaN) or establish that LTD and depotentiation have distinct underlying signaling mechanisms; its statement about different forms of plasticity concerns LTD/depotentiation versus LTP. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Zhuo et al., 1999 sourcePartly supported

  The Discussion says genetic studies of PKA implicate its signaling pathway in both LTD and depotentiation, and that the two processes have distinct mechanisms. But the Results report that LTD was normal in calcineurin Aα-deficient mice while depotentiation was impaired, so the paper does not support saying both are sensitive to that genetic manipulation of calcineurin. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Yang et al., 2009Not matched

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

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

Past work in heterologous cells demonstrated that negative regulation of recombinant GluA1 currents by AKAP79 involved dephosphorylation of S845 but not S831, required anchored CaN, and was opposed by anchored PKA.

“past work in heterologous cells demonstrated that negative regulation of recombinant GluA1 currents by AKAP79 involved dephosphorylation of S845 but not S831, required anchored CaN, and was opposed by anchored PKA”

• cites Dell'Acqua et al., 2002Not matched

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

• cites Tavalin et al., 2002 sourceSupported
• cites Hoshi et al., 2005 sourcePartly supported

  The Results (page unavailable) show that recombinant GluR1 currents run down in HEK293 cells and that loss of PP2B (calcineurin) anchoring prevents this rundown. They also link anchored PKA to Ser 845 phosphorylation and, in hippocampal neurons, to maintaining AMPA currents. The paper does not demonstrate that the current reduction specifically involves dephosphorylation of Ser 845 rather than Ser 831, or establish PKA's opposing effect in the heterologous-cell experiments. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Forebrain-specific CaN knockout mice, like ΔPIX mice, exhibit a lack of LTD but maintain normal depotentiation.

“In addition, forebrain-specific CaN knockout mice, like our ΔPIX mice, exhibit a lack of LTD but maintain normal depotentiation”

• cites Zeng et al., 2001 sourcePartly supported

  The Introduction and the passage headed “Impaired LTD But Normal LTP and Depotentiation at the Schaffer Collateral-CA1 Synapse” report diminished, not absent, LTD in the knockout mice. The depotentiation passage reports comparable responses in mutant and control slices. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

CaN activity is required for cLTD-induced F-actin depolymerization and subsequent disruption of AKAP150 binding to PSD-95 and membranes; this uncoupling may prevent PKA re-phosphorylation of GluA1 that would promote recycling after LTD.

“CaN activity is also required for cLTD-induced F-actin depolymerization and subsequent disruption of AKAP150 binding to PSD-95 and membranes (Gomez et al., 2002); this uncoupling of AKAP150 from PSD-95 and membranes may prevent PKA re-phosphorylation of GluA1 that would promote recycling after LTD”

• cites Gomez et al., 2002 sourcePartly supported

  In ‘Activation of the phosphatase calcineurin but not protein kinases is necessary for NMDA receptor regulation of AKAP79/150 targeting’ (page unavailable), calcineurin inhibitors mostly prevented NMDA-induced AKAP79/150 redistribution. The F-actin results and the ‘pathways shared with LTD’ discussion (pages unavailable) support a proposed sequence of actin remodeling, loss of association with PSD-95, and membrane release. The paper studied glutamate/NMDA-treated neurons rather than directly demonstrating this sequence during cLTD; the GluA1 recycling proposal follows the citation and is not attributed to this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Ehlers, 2000 sourceNot checked — no full text of the source
• cites Snyder et al., 2005 sourceNot checked — no full text of the source

May combine two claims.

There were no differences in spine morphology or number between WT and ΔPIX mice.

“observed no differences in spine morphology or number as quantified by spine density counts”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

Both WT and ΔPIX slices exhibited depotentiation; the relative amount of depotentiation was similar for AKAP150ΔPIX and WT.

“Both WT and ΔPIX slices exhibited depotentiation; however, while the fEPSP responses for WT slices returned to near the pre-LTP baseline after LFS, the responses in ΔPIX slices remained increased above baseline”

• Also stated in: § AKAP150-anchored CaN limits LTP but is not strictly required for synaptic depotentiation · plain

  “we renormalized the last 10 minutes of the LTP responses back to baseline, and found that the relative amount of depotentiation was similar for AKAP150ΔPIX and WT”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

Using standard 1 Hz LFS, LTD was readily detectable in WT but absent in ΔPIX mice.

“Using standard 1 Hz LFS, we found that LTD was readily detectable in WT but absent in ΔPIX mice”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

There were no significant differences in GABA-mediated sIPSC and mIPSC mean peak amplitudes or mean frequency between ΔPIX and WT.

“we studied GABA-mediated sIPSC and mIPSC (Fig. 4A) events and found no significant differences in mean peak amplitudes or mean frequency”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

There were no significant differences in action-potential dependent AMPAR-mediated sEPSCs or action-potential independent mEPSCs for mean peak amplitude or mean frequency between ΔPIX and WT.

“we found no significant differences in action-potential dependent AMPAR-mediated spontaneous activity (sEPSCs) or action-potential independent mEPSCs for either mean peak amplitude or mean frequency”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

The quote only partly states this claim.

WT slices showed an initial decrease in fEPSP slope that was not seen for ΔPIX slices using either 10 Hz or 1 Hz LFS.

“WT slices showed an initial decrease in fEPSP slope that was not seen for ΔPIX slices using either 10 Hz”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

By 60 minutes after cLTD, S845 phosphorylation recovered completely back to the higher initial level for ΔPIX while remaining ~20% decreased for WT.

“by 60 minutes after cLTD, S845 phosphorylation recovered completely back to the higher initial level for ΔPIX while remaining ~20% decreased for WT”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

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

AKAP150ΔPIX mice have no obvious alterations in physical, behavioral, or breeding phenotype in the home cage environment.

“AKAP150ΔPIX mice have no obvious alterations in physical, behavioral, or breeding phenotype in the home cage environment.”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.

May combine two claims.

The normalized I-V curve was linear for WT neurons, consistent with presence of GluA2 in most synaptic receptors, while ΔPIX neurons exhibited clear inward rectification with significantly decreased outward current at +40 mV compared to inward current at −65 mV.

“revealed an expected linear I–V curve for WT neurons, consistent with the presence of GluA2 in most synaptic receptors, while ΔPIX neurons exhibited clear inward rectification in the I–V curve, with significantly decreased outward current measured at +40 mV compared to inward current at −65 mV”

May combine two claims.

WT CA1 neurons typically displayed robust outward +40 mV and inward −65 mV AMPAR EPSCs, whereas ΔPIX CA1 neurons in general showed reduced outward compared to inward AMPAR currents, with some neurons showing particularly large differences.

“While WT CA1 neurons typically displayed robust outward +40 mV and inward −65 mV AMPAR EPSCs, ΔPIX CA1 neurons in general showed reduced outward compared to inward AMPAR currents, with some neurons showing particularly large differences”

May combine two claims.

AKAP150ΔPIX required a 70 μM NMDA-cLTD treatment to remove it from synapses, whereas AKAP150WT was efficiently removed by 30 or 50 μM NMDA.

“AKAP150ΔPIX required a 70 μM NMDA-cLTD treatment to remove it from synapses, whereas AKAP150WT was efficiently removed by 30 or 50 μM NMDA”

May combine two claims.

When AKAP150-CaN anchoring was disrupted in ΔPIX mice, enhanced LTP expression was observed immediately after induction with 1x100 Hz HFS as well as continued enhanced potentiation that was blocked by Ca2+-permeable AMPAR antagonist IEM1460.

“When AKAP150-CaN anchoring was disrupted in ΔPIX mice, we observed enhanced LTP expression immediately after induction with 1x100 Hz HFS as well as continued enhanced potentiation that was blocked by the Ca2+-permeable AMPAR antagonist IEM1460.”

May combine two claims.

In ΔPIX mice, LFS-LTD was impaired, but the same LFS protocol significantly depotentiated the enhanced LTP.

“Interestingly, in ΔPIX mice we found that LFS-LTD was impaired, but the same LFS protocol significantly depotentiated the enhanced LTP.”

May combine two claims.

GluA1 S845/831A and S845A knock-in mice are deficient in LTD, but S831A mice express normal LTD, indicating that LTD requires regulation of only S845 phosphorylation.

“GluA1 S845/831A and S845A knock-in mice are deficient in LTD, but S831A mice express normal LTD, further indicating that LTD requires regulation of only S845 phosphorylation”

• 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.

ΔPIX deletion of 655PIAIIIT661 from AKAP150 selectively eliminates CaN anchoring while leaving intact all other AKAP structural domains and functions including PKA and PKC anchoring, membrane targeting, ion channel binding, and linkage to AMPAR and NMDAR by PSD-95 family MAGUK scaffold proteins.

“Importantly, ΔPIX deletion of 655PIAIIIT661 from AKAP150 selectively eliminates CaN anchoring while leaving intact all the other AKAP structural domains and functions including PKA and PKC anchoring, membrane targeting, ion channel binding, and linkage to AMPAR and NMDAR by PSD-95 family membrane-associated guanylate kinase (MAGUK) scaffold proteins”

• AssumptionRests on an assumption: The C-terminal myc epitope tag introduced into AKAP150ΔPIX does not alter AKAP150 function or the phenotype.
• AssumptionThe authors state this as an assumption: The role of AKAP150-anchored CaN in regulating LTP or LTD in vivo and the underlying mechanisms are not sufficiently understood.

Probably not a substantial claim: may not pass S3 (load-bearing).

Brief bath application of NMDA produces a form of chemical LTD (cLTD) that is similar to homosynaptic LTD induced by LFS.

“Brief bath application of NMDA produces a form of chemical LTD (cLTD) that is similar to homosynaptic LTD induced by LFS”

• cites Kameyama et al., 1998 sourceNot checked — no full text of the source
• cites Lee et al., 1998 sourceNot checked — no full text of the source

May combine two claims.

The PIAIIIT motif is required for cellular anchoring of CaN and its deletion eliminates functional regulation of L-type voltage-gated Ca2+ channel currents and signaling to the nucleus by CaN in cultured neurons.

“This motif is required for cellular anchoring of CaN and its deletion eliminates functional regulation of L-type voltage-gated Ca2+ channel currents and signaling to the nucleus by CaN in cultured neurons”

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

Classified as probably not a substantial claim.

Protein phosphatases PP1, PP2A, and CaN dephosphorylate GluA1 S845 and remove receptors by endocytosis during LTD.

“while protein phosphatases PP1, PP2A, and CaN (also known as PP2B) dephosphorylate GluA1 S845 and remove receptors by endocytosis during LTD”

• cites Mulkey et al., 1993Not matched

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

• cites Kameyama et al., 1998 sourceNot checked — no full text of the source
• cites Lee et al., 1998 sourceNot checked — no full text of the source

May combine two claims.

Both LFS and NMDA-cLTD induce selective dephosphorylation of GluA1 S845, but not S831, through activation of CaN and other phosphatases.

“both of these stimulation methods induce selective dephosphorylation of GluA1 S845, but not S831, through activation of CaN and other phosphatases”

• cites Kameyama et al., 1998 sourceNot checked — no full text of the source
• cites Lee et al., 1998 sourceNot checked — no full text of the source

May combine two claims.

IEM1460 had no effects on LTD expression in WT slices, indicating that GluA2-lacking receptors are either prevented from entering the synapse or are quickly removed by LTD induction.

“In contrast, IEM1460 had no effects on LTD expression in WT slices, indicating that GluA2-lacking receptors are either prevented from entering the synapse or are quickly removed by LTD induction as in He et al., 2009.”

• cites He et al., 2009Not matched

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

May combine two claims.

Many GluA1 receptors may be phosphorylated by PKA prior to LTD induction; however, there is evidence that acute activation of AKAP150 anchored-PKA signaling is also required during LTD.

“Many of these GluA1 receptors may be phosphorylated by PKA prior to LTD induction (Kameyama et al., 1998; Snyder et al., 2005); however, there is evidence that acute activation of AKAP150 anchored-PKA signaling is also required during LTD”

• cites Kameyama et al., 1998 sourceNot checked — no full text of the source
• cites Snyder et al., 2005 sourceNot checked — no full text of the source
• cites Lu et al., 2008Not matched

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

May combine two claims.

Dephosphorylation and endocytosis of the extrasynaptic GluA1 pool is required for LTD, explaining why S845A knock-in mice that lack this receptor pool are deficient in LTD.

“dephosphorylation and endocytosis of this pool of GluA1 is required for LTD, explaining why S845A knock-in mice that lack this receptor pool are deficient in LTD”

• cites He et al., 2009Not matched

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

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

May combine two claims.

Enhanced basal S845 phosphorylation and impaired dephosphorylation and removal of GluA1 observed in ΔPIX mice could indicate increased synaptic contribution of Ca2+-permeable AMPARs that interfere with LTD expression.

“the enhanced basal S845 phosphorylation and impaired dephosphorylation and removal of GluA1 we observe for ΔPIX mice could indicate that there is increased synaptic contribution of Ca2+-permeable AMPAR that interfere with LTD expression”

May combine two claims.

The AMPA/NMDA ratio results suggest that ΔPIX mice may have more Ca2+-permeable AMPARs that increase synaptic inward currents at −65 mV with little impact on outward currents at +40 mV, which are carried predominantly by GluA2-containing receptors.

“these AMPA/NMDA ratio results suggest that ΔPIX mice may have more Ca2+-permeable AMPARs that increase synaptic inward currents at −65 mV with little impact on outward currents at +40 mV, which are carried predominantly by GluA2-containing receptors”

May combine two claims.

LTD is impaired in GluA1-S845A knock-in mice, where S845 phosphorylation stabilizes GluA1 homomers in extrasynaptic locations where they exchange in and out of the synapse but are removed by LTD.

“LTD is impaired in GluA1-S845A knock-in mice (Lee et al., 2010), where it was found that S845 phosphorylation stabilizes GluA1 homomers in extrasynaptic locations where they exchange in and out of the synapse but are removed by LTD”

• cites Lee et al., 2010 sourceNot checked — no full text of the source
• cites He et al., 2009Not matched

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

May combine two claims.

Using an integrated approach, the study discovered a novel role for AKAP-CaN in dephosphorylating GluA1 S845 and limiting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs to regulate not only LTD, but also LTP expression.

“Using this integrated approach we discovered a novel role for AKAP-CaN in dephosphorylating GluA1 S845 and limiting the synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs to regulate not only LTD, but also LTP expression.”

May combine two claims.

Whole-cell recording results point to increased activity of GluA1 homomers in ΔPIX CA1 neurons that could be contributing to LTP enhancement and LTD impairment if these receptors were recruited to synapses and not removed after HFS and LFS, respectively.

“These whole-cell recording results all point to increased activity of GluA1 homomers inΔPIX CA1 neurons that could be contributing to LTP enhancement and LTD impairment if these receptors were recruited to synapses and not removed after HFS and LFS, respectively.”

May combine two claims.

For ΔPIX neurons, GluA2-lacking receptors are not removed and likely replace any synaptic GluA2-containing receptors removed during LTD induction to block subsequent expression.

“In contrast, for ΔPIX neurons, GluA2-lacking receptors are not removed and likely replace any synaptic GluA2-containing receptors removed during LTD induction to block subsequent expression.”

May combine two claims.

AKAP150-CaN promotes GluA1 homomer removal, but removal of at least some GluA2-containing receptors does not strictly require CaN anchoring.

“These findings further indicate that AKAP150-CaN promotes GluA1 homomer removal, but removal of at least some GluA2-containing receptors does not strictly require CaN anchoring.”

Classified as probably not a substantial claim.

The inward rectification of GluA2-lacking receptors is due to voltage-dependent block of the channel pore at depolarized membrane potentials by intracellular polyamines.

“The inward rectification of GluA2-lacking receptors is due to voltage-dependent block of the channel pore at depolarized membrane potentials by intracellular polyamines”

• cites Rozov et al., 1998 sourceNot checked — no full text of the source

May combine two claims.

During LTD, S845 is dephosphorylated by activation of CaN, PP1 and PP2A, removed from synapses, and endocytosed from the extrasynaptic membrane.

“During LTD, S845 is dephosphorylated by activation of CaN, PP1 and PP2A, removed from synapses, and endocytosed from the extrasynaptic membrane”

• cites Lee et al., 1998 sourceNot checked — no full text of the source
• 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.

Based on the increased average rectification index, GluA2-lacking receptors may have either partially replaced GluA2-containing receptors at most ΔPIX synapses or more completely replaced them at a subset of synapses.

“based on the increased average rectification index they may have either been partially replaced by GluA2-lacking receptors at most synapses or perhaps more completely replaced at a subset of synapses”

May combine two claims.

The limited knock-in mutation minimized problems associated with complete AKAP150 knockout, which simultaneously removes multiple and opposing functions (both PKA and CaN anchoring) and thus limits phenotypic impacts and mechanistic interpretations.

“This knock-in minimized problems associated with complete AKAP150 knockout, which simultaneously removes multiple and opposing functions (i.e. both PKA and CaN anchoring) and thus limits phenotypic impacts and mechanistic interpretations.”

May combine two claims.

1 x 100 Hz LTP requires PKA activity, recruits GluA2-lacking AMPARs, and is impaired in PKA-anchoring deficient AKAP150D36 mice that are >8 weeks-old but not 3-4 weeks-old.

“In particular, 1 x 100 Hz LTP requires PKA activity, recruits GluA2-lacking AMPARs, and is impaired in PKA-anchoring deficient AKAP150D36 mice that are >8 weeks-old but not 3–4 weeks-old”

• cites Lu et al., 2007Not matched

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

May combine two claims.

AKAP150-CaN is very specifically targeted to regulate S845, and the amount of LTP that is refractory to depotentiation in ΔPIX mice is likely due to an inability to dephosphorylate S845 and fully suppress the activity of IEM-sensitive GluA2-lacking receptors that are aberrantly recruited during LTP.

“These findings reinforce that AKAP150-CaN is very specifically targeted to regulate S845, and suggest that the amount of LTP that is refractory to depotentiation in ΔPIX mice is likely due to an inability to dephosphorylate S845 and fully suppress the activity of IEM-sensitive GluA2-lacking receptors that are aberrantly recruited during LTP.”

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

The differences in LTP results could be due to age differences; CaN knockout and S831,845D mice were studied at older ages of 4-6 weeks.

“These differences could be due to age differences; CaN knockout and S831,845D mice were studied at older ages of 4–6 weeks.”

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

At the younger age, AKAP-CaN may not only oppose PKA anchored to AKAP150, but also other pools of PKA and perhaps other kinases to limit LTP expression.

“Thus, at the younger age AKAP-CaN may not only oppose PKA anchored to AKAP150, but also other pools of PKA and perhaps other kinases to limit LTP expression.”

May combine two claims.

While AKAP150-anchored CaN is involved in S845 dephosphorylation in LTD, it may be redundant with other phosphatase pathways that dephosphorylate S831 during depotentiation.

“Thus, while AKAP150-anchored CaN is clearly involved in S845 dephosphorylation in LTD, it may be redundant with other phosphatase pathways that dephosphorylate S831 during depotentiation.”

May combine two claims.

The current results could also indicate that AKAP anchored-CaN plays a more important role in limiting the strength of potentiated response after LTP by opposing phosphorylation of S845 and regulating AMPAR subunit composition rather than in setting the induction threshold, which may involve other pools of CaN and additional substrates.

“Nonetheless, our current results could also indicate that AKAP anchored-CaN plays a more important role in limiting the strength of potentiated response after LTP by opposing phosphorylation of S845 and regulating AMPAR subunit composition rather than in setting the induction threshold, which may involve other pools of CaN and additional substrates.”

May combine two claims.

Earlier studies hinted at a role for AKAP79/150-anchored CaN in regulation of Ca2+-permeable GluA1 homomers that the present results now clearly establish as a key mechanism that maintains bi-directional synaptic plasticity in the hippocampus.

“Thus, these earlier studies hinted at a role for AKAP79/150-anchored CaN in regulation of Ca2+-permeable GluA1 homomers that our results here now clearly establish as a key mechanism that maintains bi-directional synaptic plasticity in the hippocampus.”

May combine two claims.

LTD causes dephosphorylation of the GluA1 S845 PKA site, while depotentiation triggers dephosphorylation of the GluA1 S831 CaMKII/PKC site.

“LTD causes dephosphorylation of the GluA1 S845 PKA site, while depotentiation triggers dephosphorylation of the GluA1 S831 CaMKII/PKC site”

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