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Cited by 1,139Neuroscience and Neuropharmacology ResearchNeural dynamics and brain functionGenetics and Neurodevelopmental Disorders

Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function

Open access
Turrigiano, G.·2012·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a005736PMC PMC3249629
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Abstract

Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development. Recent work has shown that these destabilizing influences are counterbalanced by homeostatic plasticity mechanisms that act to stabilize neuronal and circuit activity. One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms may allow local changes in synaptic activation to generate local synaptic adaptations, and network-wide changes in activity to generate network-wide adjustments in the balance between excitation and inhibition. The signaling pathways underlying these various forms of homeostatic plasticity are currently under intense scrutiny, and although dozens of molecular pathways have now been implicated in homeostatic plasticity, a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged. On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.

AI snapshot

Written from the paper’s full text.

TL;DR

Homeostatic synaptic plasticity stabilizes neuronal firing through mechanisms such as synaptic scaling, which uses calcium-dependent sensors to bidirectionally regulate glutamate receptor accumulation at synapses. The review distinguishes global, cell-autonomous scaling from local/quasi-local and network-level mechanisms, and highlights that the molecular logic of homeostatic feedback remains incompletely understood.

Key findings

  • Synaptic scaling is a cell-autonomous, global form of homeostatic plasticity: perturbing activity bidirectionally scales quantal amplitude (mEPSC/mini amplitude) up or down, regulating both AMPA and NMDA currents proportionally, and requires the GluA2 subunit of AMPARs.
  • Scaling up and scaling down share some calcium/CaMKK/CaMKIV signaling but diverge in other molecular requirements; for example, scaling up depends completely on PSD-95, whereas scaling down can be supported by either PSD-95 or PSD-93.
  • Local or quasi-local homeostatic mechanisms also exist: combined TTX and glutamate receptor block locally enhances GluA1-containing/GluA2-lacking AMPAR insertion via retinoic acid/RARα, and presynaptic release probability can be regulated quasi-locally by dendritic depolarization.
  • Network-level and secreted-factor mechanisms contribute to excitation/inhibition balance: BDNF and glial TNFα are implicated, with TNFα suggested to be permissive/maintenance rather than instructive for scaling; in vivo visual deprivation can scale mEPSC amplitude and insert GluA2-containing AMPARs.

Methods

  • This is a review article, not a primary experimental study; it synthesizes findings from in vitro and in vivo work on homeostatic synaptic plasticity at the neuromuscular junction and central mammalian synapses.
  • The paper reviews signaling pathways, expression mechanisms, and functional roles of synaptic scaling, local/quasi-local plasticity, secreted factors, and synapse-type-specific rules.
  • No new experimental sample, dataset, or statistical analysis is reported.

Limitations

  • Stated: the signaling pathways underlying homeostatic plasticity are under intense scrutiny, but “a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged.”
  • Stated: whether mechanisms underlying synaptic scaling in vivo and in other brain regions are similar to or distinct from those in cultured cortical neurons remains an open question.
  • Stated: local homeostatic regulation remains controversial, and the physiological significance of some presynaptic changes, such as VGlut changes, remains to be determined. Evident: as a narrative review, it does not systematically quantify evidence or resolve conflicting findings across studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a005736

Cites

109 of 109 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

61 of 157 cited sources checked · 33 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Scaling up can also be induced by chronic changes in the level of depolarization in a BDNF-independent manner.

    “However, scaling up can also be induced by chronic changes in the level of depolarization in a BDNF-independent manner (Leslie et al. 2001), and the relationship between BDNF-mediated synaptic scaling and cell-autonomous synaptic scaling of excitatory inputs (Ibata et al. 2008) remains unclear.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Leslie et al. 2001 source

      The Abstract (page unavailable) says chronic depolarization reduced excitatory quantal amplitude in a BDNF-independent manner—the opposite of scaling up. It attributes scaling up to low levels of BDNF, and the Discussion likewise distinguishes the BDNF-dependent increase from the depolarization-induced decrease. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Small changes in the balance between excitation and inhibition can have major effects on ongoing activity.

    “Central neurons are embedded in complex networks composed of many cell types, including both excitatory and inhibitory neurons, and small changes in the balance between excitation and inhibition can have major effects on ongoing activity (Nelson and Turrigiano 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Nelson and Turrigiano 2008 source

      The Inhibitory Plasticity section discusses balancing excitation and inhibition, and the Homeostatic Plasticity section says changes in synaptic strength can alter neuronal activity. The copy does not establish the more specific claim that small shifts in excitation–inhibition balance have major effects on ongoing activity. Page numbers are unavailable in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Loss of synaptic innervation initiates an increase in muscle excitability through changes in postsynaptic receptor number and localization.

    “where it was observed that loss of synaptic innervation initiated an increase in muscle excitability through changes in postsynaptic receptor number and localization.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Berg and Hall, 1975 source

      The Abstract reports that chronic neuromuscular blockade increased extrajunctional acetylcholine-receptor binding and sensitivity in rat muscle, with changes similar to those after denervation. But the nerve remained active during blockade, so the paper does not establish that loss of synaptic innervation initiated the change or that receptor changes caused increased muscle excitability. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Sharpless 1975
  • Premisecitation

    Synaptic scaling allows neurons to detect changes in their own firing rates through calcium-dependent sensors that regulate receptor trafficking to increase or decrease accumulation of glutamate receptors at synaptic sites.

    “One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Turrigiano et al. 1998 source
    • cites Gainey et al. 2009 source

      The Introduction says that a drop in postsynaptic firing leads to AMPA-receptor accumulation at synapses, and the Discussion describes synaptic strengths scaling up or down in response to chronic changes in activity. The paper also links scaling to receptor trafficking, but the passages do not identify calcium-dependent sensors that detect firing-rate changes or regulate that trafficking. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationreasoning

    The firing rate set point is an emergent property that represents the stable point of all the opposing signaling pathways that operate on synaptic strength.

    “One interesting implication of this model is that the firing rate set point is an emergent property that represents the stable point of all the opposing signaling pathways that operate on synaptic strength (Turrigiano 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Turrigiano 2008 source

      In Concluding Remarks, the paper proposes that the activity set point could arise where opposing forces regulating receptor accumulation equalize. The citing sentence presents this proposed model as fact and extends it to all opposing signaling pathways that affect synaptic strength, which the passage does not establish. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    Scaling up is completely dependent on the scaffold protein PSD-95, whereas scaling down can be supported by either PSD-95 or PSD-93.

    “Further, whereas scaling up is completely dependent on the scaffold protein PSD-95, scaling down can be supported by either PSD-95 or PSD-93 (Sun and Turrigiano 2011).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sun and Turrigiano 2011 source

      The Discussion states the reverse: scaling down is critically dependent on PSD-95, while scaling up can be supported by either PSD-95 or PSD-93 in young neurons. The Results section ‘PSD-95 is necessary for scaling down’ likewise says PSD-93 cannot compensate for loss of PSD-95 during scaling down. The paper adds that scaling up becomes dependent on PSD-95 in older neurons. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Postsynaptic knockdown of GluA2 completely blocks synaptic scaling, suggesting that if there is a presynaptic change in transmitter packaging it is not sufficient to enhance mini amplitude on its own.

    “It is worth noting, however, that postsynaptic knockdown of GluA2 is able to completely block synaptic scaling (Gainey et al. 2009), suggesting that if there is a presynaptic change in transmitter packaging it is not sufficient to enhance mini amplitude on its own.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gainey et al. 2009 source

  • May combine two claims.

    Interpretationcitation

    Given that postsynaptic and presynaptic responses to activity deprivation can occur independently, they likely represent distinct forms of plasticity induced by distinct signaling pathways.

    “Given that the postsynaptic and presynaptic responses to activity deprivation can occur independently (Wierenga et al. 2005(Wierenga et al. , 2006)), it is likely that they represent distinct forms of plasticity induced by distinct signaling pathways.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Wierenga et al. 2005 source
    • cites Wierenga et al. 2006 source

  • May combine two claims.

    Premisecitation

    Scaling down in response to elevated network activity is a cell-autonomous function of postsynaptic firing, and involves enhanced calcium influx, gene transcription, the CaMKK/CaMKIV signaling pathway, and targets the GluA2 subunit.

    “Like scaling up, scaling down in response to elevated network activity is a cell-autonomous function of postsynaptic firing, and involves enhanced calcium influx (Fig. 2), gene transcription, the CaMKK/CaMKIV signaling pathway, and targets the GluA2 subunit (Goold and Nicoll 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Goold and Nicoll 2010 source

      The Discussion reports that cell-autonomous excitation drives calcium-dependent synaptic depression through CaMKK/CaMK4. It also limits the transcription and GluA2 requirements to AMPAR depression: NMDAR depression does not require them. The citing sentence omits that distinction when describing scaling down generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Lowering presynaptic firing with an inwardly rectifying Kir channel selectively enhances accumulation of GluA1 at postsynaptic sites, suggesting existence of a synapse-specific form of homeostatic compensation to reduced receptor activation.

    “Lowering presynaptic firing with an inwardly rectifying K ir channel was observed to selectively enhance the accumulation of GluA1 at postsynaptic sites, suggesting the existence of a synapse-specific form of homeostatic compensation to reduced receptor activation (Hou et al. 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Hou et al. 2008 source

  • May combine two claims.

    Premisecitation

    The same manipulation (activity blockade using TTX or AMPAR antagonists) that only affects mini amplitude in young cultures can also induce changes in mini frequency and presynaptic release probability in older neuronal cultures, through a process involving postsynaptic hyperpolarization and a drop in calcium influx.

    “Interestingly, the same manipulation (activity blockade using TTX or AMPAR antagonists) that only affects mini amplitude in young cultures (Turrigiano et al. 1998;Wierenga et al. 2005) can also induce changes in mini frequency and in presynaptic release probability in older neuronal cultures (Wierenga et al. 2006), through a process that involves postsynaptic hyperpolarization and a drop in”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Turrigiano et al. 1998 source
    • cites Wierenga et al. 2005 source
    • cites Wierenga et al. 2006 source

  • May combine two claims.

    Premisecitation

    BDNF, Arc, TNFa, MHC1, b3 integrins, PICK1, and scaffold proteins PSD-95 and PSD-93 can all contribute to, or are essential for, synaptic scaling in dissociated cultures.

    “Additionally, there is evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) (Rutherford et al. 1998), the immediate early gene Arc (Shepherd et al. 2006), the cytokine TNFa (Stellwagen and Malenka 2006;Steinmetz and Turrigiano, 2010), the immune molecule MHC1 (Goddard et al. 2007), b3 integrins (Cingolani et al. 2008), the AMPAR binding protein PICK1 (Anggono et al. 2011), and”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Rutherford et al. 1998 source
    • cites Shepherd et al. 2006 source
    • cites Stellwagen and Malenka 2006;Steinmetz and Turrigiano, 2010

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

  • May combine two claims.

    Premisecitation

    Chronic hyperpolarization of an entire neuron by expression of an inwardly rectifying K channel does not induce postsynaptic scaling, suggesting that chronic global hyperpolarization of neuronal dendrites and somata overrides the signals that induce scaling up in response to a drop in firing.

    “Interestingly, chronic hyperpolarization of an entire neuron by expression of an inwardly rectifying K channel (K ir ) does not induce postsynaptic scaling (Burrone et al. 2002;Hou et al. 2008), suggesting that chronic global hyperpolarization of neuronal dendrites and somata overrides the signals that induce scaling up in response to a drop in firing.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Burrone et al. 2002 source
    • cites Hou et al. 2008 source

      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

  • May combine two claims.

    Premisecitation

    Activity-dependent BDNF release is critical for scaling of inhibitory synapses onto pyramidal neurons and for homeostatic regulation of excitatory synapses onto inhibitory neurons.

    “A number of reports have suggested that activity-dependent BDNF release is critical for scaling of inhibitory synapses onto pyramidal neurons as well as the homeostatic regulation of excitatory synapses onto inhibitory neurons (Rutherford et al. 1997(Rutherford et al. , 1998;;Copi et al. 2005;Swanwick et al. 2006).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Rutherford et al. 1997 source

      The Discussion reports that activity blockade reduces inhibition onto cortical pyramidal neurons and that exogenous BDNF prevents this reduction, supporting the inhibitory part of the claim. It infers reduced endogenous BDNF production rather than directly demonstrating activity-dependent release, and it does not establish homeostatic regulation of excitatory synapses onto inhibitory neurons; the excitatory currents it mentions are onto pyramidal neurons. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Rutherford et al. 1998 source
    • cites Copi et al. 2005 source

  • May combine two claims.

    Premisecitation

    TNFa signaling is not necessary for induction of early (6 h) scaling, but becomes essential for maintenance of scaling during prolonged (>24 h) activity blockade.

    “TNFa signaling was not necessary for the induction of early (6 h) scaling, but became essential for maintenance of scaling during prolonged (.24 h) activity blockade.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Steinmetz and Turrigiano 2010 source

  • May combine two claims.

    Premisecitation

    Acute application of TNFa or conditioned media from activity-blocked cultures increases mEPSC amplitude.

    “This model is based on the observations that TNFa levels are elevated by prolonged (48 h) activity blockade, acute application of TNFa (or conditioned media from activity-blocked cultures) increases mEPSC amplitude, and scaling up in response to prolonged activity blockade is prevented by blocking TNFa signaling (Beattie et al. 2002;Stellwagen et al. 2005;Stellwagen and Malenka 2006).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Beattie et al. 2002 source
    • cites Stellwagen et al. 2005 source

      The culture electrophysiology methods (page not provided) say TNFα was applied 15–25 minutes before recording, and the Figure 5 caption reports a significant increase in mEPSC amplitude in TNFα-treated cultures. The passages do not support the separate claim about conditioned media from activity-blocked cultures. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Stellwagen and Malenka 2006 source

  • May combine two claims.

    Premisecitation

    Synapses onto the same dendrite tend to have similar Pr, and there is an inverse relationship between synapse number and Pr onto individual dendrites, suggesting that this regulation happens in a quasi-local manner as a result of the degree of dendritic depolarization.

    “Synapses onto the same dendrite tended to have similar P r , and there was an inverse relationship between synapse number and P r onto individual dendrites, suggesting that this regulation happens in a”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Branco et al. 2008 source

      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

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

    Premisecitation

    A positive correlation between Pr and synaptic strength at cortical synapses has been reported, but because in these studies synaptic strength was measured at unitary connections, it remains an open possibility that an inverse correlation exists at the level of summed dendritic input.

    “In apparent conflict with this model, a positive correlation between P r and synaptic strength at cortical synapses has been reported (Hardingham et al. 2010;Kay et al. 2011), but because in these studies synaptic strength was measured at unitary connections, it remains an open possibility that such an inverse correlation exists at the level of summed dendritic input.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Hardingham et al. 2010 source
    • cites Kay et al. 2011 source

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

      Experimental — accuracy not yet measured

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

    Premisecitation

    This quasi-local (dendrite-wide) form of presynaptic homeostasis has been suggested to prevent synaptic saturation owing to strong depolarization from summed inputs onto a dendrite, by reducing Pr when postsynaptic activation rises too high.

    “This quasi-local (dendrite-wide) form of presynaptic homeostasis has been suggested to prevent synaptic saturation owing to strong depolarization from summed inputs onto a dendrite, by reducing P r when postsynaptic activation rises too high (Branco et al. 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Branco et al. 2008 source

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

    Premisecitation

    BDNF was the first secreted factor suggested to play a role in homeostatic plasticity.

    “BDNF was the first such secreted factor suggested to play a role in homeostatic plasticity (Rutherford et al. 1997(Rutherford et al. , 1998)).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Rutherford et al. 1997 source

      The Discussion (page not specified in our copy) says BDNF regulates inhibition in cortical cultures and may help reduce inhibition when activity falls too low, supporting a role in homeostatic plasticity. The paper does not establish the historical claim that BDNF was the first secreted factor suggested to have that role. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Rutherford et al. 1998 source

  • May combine two claims.

    Interpretationcitation

    Scaling and TNFa are neither additive nor simply occlusive.

    “Unlike TTX treatment, acute TNFa application does not scale up mini amplitude and adding TNFa to prescaled synapses actually reduces synaptic strength, indicating that scaling and TNFa are neither additive nor simply occlusive (Steinmetz and Turrigiano 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Steinmetz and Turrigiano 2010 source

  • May combine two claims.

    Premisecitation

    Dark rearing increases the abundance of GluA2-lacking receptors and requires GluA1 phosphorylation.

    “In contrast, dark rearing increases the abundance of GluA2-lacking receptors and requires GluA1 phosphorylation, suggesting that these two modes of deprivation may induce different forms of compensatory synaptic plasticity (Goel and Lee 2007;Goel et al. 2011).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Goel and Lee 2007 source

      The Results section (page unavailable) reports that two days of dark rearing increased AMPA receptor-mediated mEPSC amplitude in mouse visual cortex. The Discussion (page unavailable) says dark rearing increased GluR1 (GluA1) phosphorylation, but our copy does not establish that phosphorylation is required or that GluA2-lacking receptors become more abundant. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Goel et al. 2011 source

      The Results report that two days of dark exposure increased functional calcium-permeable AMPA receptors, consistent with more GluA2-lacking receptors; the Discussion says deprivation-induced synaptic changes require GluA1 phosphorylation. But the Methods specify that mice were raised under normal lighting until postnatal day 21, then exposed to darkness for two days. The paper does not establish these effects for dark rearing from birth. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Binocularly driven neurons maintain a similar average level of combined responsiveness to the two eyes, suggesting the drop in deprived eye responsiveness is compensated by an increase in nondeprived eye responsiveness.

    “Interestingly, binocularly driven neurons maintained a similar average level of combined responsiveness to the two eyes, suggesting that the drop in deprived eye responsiveness was compensated by an increase in nondeprived eye responsiveness (Mrsic-Flogel et al. 2007); a very similar response homeostasis following visual deprivation has been reported at retinotectal synapses (Chandrasekaran et al.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mrsic-Flogel et al. 2007 source

  • May combine two claims.

    Premisecitation

    When one eye is deprived of patterned vision during the classical critical period using lid suture, cortical neurons rapidly (within 2 or 3 days) lose responsiveness to the deprived eye, and then more slowly (over 4-6 days) gain responsiveness to the nondeprived eye.

    “When one eye is deprived of patterned vision during the classical critical period (using lid suture) there is a change in the ability of the two eyes to drive neurons within the binocular portion of visual cortex: cortical neurons rapidly (within 2 or 3 days) lose responsiveness to the deprived eye, and then more slowly (over 4 -6 days) gain responsiveness to the nondeprived eye (Frenkel and Bear”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Frenkel and Bear 2004 source
    • cites Mrsic-Flogel et al. 2007 source

      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 Kaneko et al. 2008 source

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

    Premisecitation

    The same visual deprivation paradigm that scales minis up in younger mice produces nonmultiplicative changes in minis in older mice.

    “This possibility is raised by the finding that the same visual deprivation paradigm that scales minis up in younger mice produces nonmultiplicative changes in minis in older mice, suggesting that not all synapses are affected equally (Goel and Lee 2007); however, this could also reflect the simultaneous activation of synaptic scaling and Hebbian, synapse-specific mechanisms (see Turrigiano 2011”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Goel and Lee 2007 source

  • May combine two claims.

    Premisecitation

    Visual deprivation induced by optic nerve block scales up mEPSC amplitude in vivo as in vitro, and results in insertion of GluA2-containing AMPAR.

    “Visual deprivation induced by optic nerve block scale ups mEPSC amplitude in vivo as in vitro, and results in insertion of GluA2-containing AMPAR (Desai et al. 2002;Maffei and Turrigiano 2008;Gainey et al. 2009).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Desai et al. 2002 source
    • cites Maffei and Turrigiano 2008 source

      The Results section on experience-dependent plasticity at excitatory layer 2/3 synapses reports that visual deprivation by intraocular TTX injection increased AMPA mEPSC amplitude in rats. The paper does not establish an in vitro comparison or report insertion of GluA2-containing AMPARs, so those parts of the sentence are unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Gainey et al. 2009 source

  • May combine two claims.

    Premisecitation

    In visual cortex, expression of synaptic scaling is developmentally regulated: it is expressed by layer 4 pyramidal neurons early in postnatal development, then turns off in layer 4 and begins in layer 2/3 around the opening of the classical visual system critical period, persisting into adulthood.

    “In visual cortex the expression of synaptic scaling is developmentally regulated (Desai et al. 2002;Maffei et al. 2004Maffei et al. , 2006;;Maffei and Turrigiano 2008); synaptic scaling is expressed by pyramidal neurons in layer 4 early in postnatal development, but then turns off in layer 4 and begins to be expressed in layer 2/3 pyramidal neurons around the opening of the classical visual system”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Desai et al. 2002 source
    • cites Maffei and Turrigiano 2008 source
    • cites Goel and Lee 2007 source

      The Discussion (page unavailable) reports scaling in layer 4 at P14–P16 but not P21–P23, with the opposite pattern in layer 2/3; it also says the authors’ data extend layer 2/3 plasticity through adulthood. Our copy does not establish that the switch coincides with the opening of the classical visual critical period, or identify the early layer 4 cells specifically as pyramidal neurons. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In Drosophila, reductions in glutamate receptor function or chronic hyperpolarization of the muscle lead to compensatory increases in transmitter release that restore evoked transmission to control levels.

    “For example, reductions in glutamate receptor function, or chronic hyper-polarization of the muscle, lead to compensatory increases in transmitter release that restore evoked transmission to control levels (Paradis et al. 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Paradis et al. 2001 source

  • May combine two claims.

    Premisecitation

    When cortical or hippocampal neurons are induced to fire more than normal, over many hours firing returns to baseline levels; if neuronal firing is reduced over time, neurons compensate and firing is restored.

    “When cortical or hippocampal neurons are induced to fire more than normal, over many hours firing returns to baseline levels, and similarly, if neuronal firing is reduced over time, neurons compensate and again firing is restored (Fig. 1A) (Turrigiano et al. 1998;Burrone et al. 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Turrigiano et al. 1998 source
    • cites Burrone et al. 2002 source

  • May combine two claims.

    Interpretationreasoning

    Without forces preventing the excitability of the postsynaptic neuron from changing in response to correlation-based plasticity, specificity breaks down and information can no longer be effectively stored through differences in synaptic strengths.

    “Thus, without forces that prevent the excitability of the postsynaptic neuron from changing in response to correlation-based plasticity mechanisms, their specificity breaks down and information can no longer be effectively stored through differences in synaptic strengths.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Neuronal networks likely use a complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.

    “On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Perturbations in postsynaptic function can lead to compensatory changes in presynaptic release, and vice versa, at mammalian and invertebrate NMJ.

    “More recently work at the mammalian and invertebrate NMJ has shown that perturbations in postsynaptic function can lead to compensatory changes in presynaptic release, and vice versa (Davis and Bezprozvanny 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Davis and Bezprozvanny 2001 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    For many phenomena theoretically capable of serving a homeostatic function, such a function has not been directly shown.

    “Although all of these phenomena are theoretically capable of serving a homeostatic function, for many of them such a function has not been directly shown.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cell-autonomously induced synaptic scaling is fundamentally different from LTP and LTD: it operates over a longer temporal scale (hours), a wider spatial scale (global), and utilizes distinct trafficking steps and molecular machinery to enhance or reduce synaptic accumulation of GluA2-containing AMPAR at most if not all synapses onto a neuron.

    “Thus, cell-autonomously induced synaptic scaling is fundamentally different from LTP and LTD: it operates over a longer temporal scale (hours), a wider spatial scale (global), and utilizes distinct trafficking steps and molecular machinery to enhance or reduce the synaptic accumulation of GluA2-containing AMPAR at most if not all synapses onto a neuron.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The ability of synapses to undergo postsynaptic homeostatic regulation as a function of purely local changes in transmitter release and receptor activation remains controversial and may require either extreme presynaptic hyperpolarization or a situation in which spiking and transmitter release are both severely impaired.

    “The ability of synapses to undergo postsynaptic homeostatic regulation as a function of purely local changes in transmitter release and receptor activation thus remains controversial and may require either extreme presynaptic hyperpolarization (such as would be obtained with presynaptic expression of K ir ) or a situation in which spiking and transmitter release are both severely impaired (see”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Theoretical work has suggested that quasi-local forms of homeostasis that act on groups of nearby synapses can serve a useful normalization function without severely disrupting Hebbian plasticity.

    “On the other hand, theoretical work has suggested that quasi-local forms of homeostasis that act on groups of nearby synapses can serve a useful normalization function without severely disrupting Hebbian plasticity (Rabinowitch and Segev 2006a,b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rabinowitch and Segev 2006a,b

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

  • May combine two claims.

    Interpretationreasoning

    A drop in somatic calcium influx will simultaneously enhance signaling in pathways that scale synapses up and reduce signaling in pathways that scale synapses down, and vice versa when firing rises.

    “This suggests that a drop in somatic calcium influx will simultaneously enhance signaling in the pathways that scale synapses up and reduce signaling in the pathways that scale synapses down, and vice versa when firing rises.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Synaptic scaling protocols homeostatically regulate both the NMDA and AMPA component of glutamatergic synaptic currents, and the change in AMPA and NMDA currents are proportional at individual synapses.

    “Interestingly, synaptic scaling protocols homeostatically regulate both the NMDA and the AMPA component of glutamatergic synaptic currents, and the change in AMPA and NMDA currents are proportional at individual synapses (Watt et al. 2000;Perez-Otano and Ehlers 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Watt et al. 2000 source
    • cites Perez-Otano and Ehlers 2005 source

  • May combine two claims.

    Interpretationreasoning

    Postsynaptic scaling allows neurons to stabilize activity without changing the relative strength of synaptic inputs, thus avoiding disruption of information storage or processing mechanisms that rely on differences in synaptic weights.

    “Such a postsynaptic scaling process has the attractive property of allowing neurons to stabilize activity without changing the relative strength of synaptic inputs, thus avoiding disrupting information storage or processing mechanisms that rely on differences in synaptic weights (Fig. 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The locus of change during homeostatic plasticity has important consequences for circuit function, because presynaptic changes in release probability affect short-term plasticity and dynamics of information transfer, whereas postsynaptic changes in receptor accumulation can scale postsynaptic responsiveness without affecting short-term dynamics.

    “The locus of change during homeostatic plasticity has important consequences for circuit function, because (for example) presynaptic changes in release probability will strongly affect short-term plasticity and thus the dynamics of information transfer across synapses, whereas a postsynaptic change in receptor accumulation can scale postsynaptic responsiveness without affecting the short-term”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abbott and Nelson 2000 source

  • May combine two claims.

    Premisecitation

    Selectively blocking firing by microperfusion of TTX to the soma of individual neurons scales up synaptic strengths to the same degree as blockade of network activity, whereas local block of synaptic transmission does not induce a local enhancement of receptor accumulation.

    “Selectively blocking firing by microperfusion of TTX to the soma of individual neurons scales up synaptic strengths to the same degree as blockade of network activity, whereas local block of synaptic transmission does not induce a local enhancement of receptor accumulation (Ibata et al. 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ibata et al. 2008 source

  • May combine two claims.

    Premisecitation

    In dissociated cortical cultures, excitatory synapses onto excitatory pyramidal neurons are scaled up by activity blockade, whereas excitatory synapses onto GABAergic interneurons are not.

    “In dissociated cortical cultures it has been shown that excitatory synapses onto excitatory pyramidal neurons are scaled up by activity blockade, whereas excitatory synapses onto GA-BAergic interneurons are not (Rutherford et al. 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rutherford et al. 1998 source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If this mechanism operates in vivo, it predicts an inverse relationship between Pr and the summed synaptic strength onto a dendritic branch.

    “If this mechanism operates in vivo, it predicts an inverse relationship between P r and the summed synaptic strength onto a dendritic branch.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chronic hyperpolarization of entire neurons (including dendrites) results in enhanced Pr, suggesting that Pr can be bidirectionally regulated by changes in the amount of dendritic depolarization.

    “This is consistent with evidence that chronic hyperpolarization of entire neurons (including dendrites) results in enhanced P r (Burrone et al. 2002), suggesting that P r can be bidirectionally regulated by changes in the amount of dendritic depolarization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Burrone et al. 2002 source

  • May combine two claims.

    Premisecitation

    Blocking BDNF signaling mimics the effects of activity blockade on excitatory minis, and exogenous BDNF application prevents them.

    “Blocking BDNF signaling mimics, and exogenous BDNF application prevents, the effects of activity blockade on excitatory minis, suggesting that in neocortical neurons activitydependent BDNF release could mediate synaptic scaling (Rutherford et al. 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rutherford et al. 1998 source

  • May combine two claims.

    Premisecitation

    BDNF is released as a function of pyramidal neuron activity and activates Trk receptors on both pyramidal and interneurons.

    “BDNF is thought to be released as a function of pyramidal neuron activity, and activates Trk receptors on both pyramidal and interneurons (Lu 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lu 2003

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

  • May combine two claims.

    Premisecitation

    Prolonged activity blockade with TTX increases glial release of TNFa, which acts on neurons to enhance AMPAR insertion and scale up mEPSC amplitude.

    “It was recently proposed that prolonged activity blockade (with TTX) increases glial release of TNFa, which then acts on neurons to enhance AMPAR insertion and scale up mEPSC amplitude (Stellwagen and Malenka 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stellwagen and Malenka 2006 source

  • May combine two claims.

    Interpretationreasoning

    Distinct plasticity rules at different classes of excitatory and inhibitory synapse are consistent with an overall homeostatic shift in the balance between excitation and inhibition, because the net effect of activity blockade is to enhance excitation and reduce inhibition, restoring network excitability.

    “These distinct plasticity rules at different classes of excitatory and inhibitory synapse are consistent with an overall homeostatic shift in the balance between excitation and inhibition, as the net effect of the changes induced by activity blockade are to enhance excitation and reduce inhibition, which will act to restore network excitability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In hippocampal networks, CA1 neurons scale synapses up in response to activity blockade, whereas CA3 neurons do not.

    “Interestingly, not all excitatory neurons in cortical networks express synaptic scaling.In hippocampal networks CA1 neurons scale synapses up in response to activity blockade, whereas CA3 neurons do not (Kim and Tsien 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim and Tsien 2008 source

  • May combine two claims.

    Premisecitation

    In visual cortical microcircuits, the locus of homeostatic plasticity changes as the circuit matures: early in postnatal development layer 4 responds homeostatically to brief (2 days) inactivation of the optic nerve with TTX, whereas later this response turns off in layer 4 and migrates to layers 2/3, where it persists into adulthood.

    “Interestingly, in visual cortical microcircuits the locus of homeostatic plasticity changes as the circuit matures.Early in postnatal development layer 4 (the first input layer to cortex, and the first layer to mature) responds homeostatically to brief (2 days) inactivation of the optic nerve with TTX (Desai et al. 2002;Maffei et al. 2004), whereas later (at the opening of the classical visual”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Desai et al. 2002 source
    • cites Maffei et al. 2004 source
    • cites Maffei et al. 2006 source

  • May combine two claims.

    Premisecitation

    When sensory drive to primary visual cortex is lowered in vivo, connections from fast-spiking basket cells onto layer 4 pyramidal neurons are reduced in amplitude, whereas connections from another class of interneuron become sparser but stronger.

    “When sensory drive to primary visual cortex is lowered in vivo, connections from fast-spiking basket cells onto layer 4 pyramidal neurons are reduced in amplitude, whereas connections from another class of interneuron become sparser but stronger (Maffei et al. 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maffei et al. 2004 source

  • May combine two claims.

    Premisecitation

    In visual cortex during the second and third postnatal weeks when synaptogenesis is high, there is an inverse relationship between frequency and amplitude of mEPSCs onto pyramidal neurons, and this can be prevented by raising animals in the dark.

    “Similarly, in visual cortex during the second and third postnatal weeks when synaptogenesis is high, there is an inverse relationship between the frequency and amplitude of mEPSCs onto pyramidal neurons, and this can be prevented by raising animals in the dark (Desai et al. 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Desai et al. 2002 source

  • May combine two claims.

    Interpretationreasoning

    This family of mechanisms contributes to the ability of central neuronal networks to maintain stable function and enables networks to maintain the specificity of synaptic changes that encode information.

    “Neurons and networks use a family of homeostatic synaptic plasticity mechanisms to stabilize firing rates in the face of developmental or learning-induced changes in drive, and this contributes to the ability of central neuronal networks to maintain stable function and enables networks to maintain the specificity of synaptic changes that encode information.”
    Quote in the paperSubstantial claim
48 of 48

  • The paper relies on this without support.

    Neural circuits must maintain stable function in the face of plastic challenges including changes in synapse number and strength during learning and development.

    “Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development.”

  • The paper relies on this without support.

    At the neuromuscular junction, as muscle fibers grow, motor neurons must remain capable of bringing them over threshold for contraction.

    “The stability problem at the neuromuscular junction (NMJ) is fairly simple: As muscle fibers grow, motor neurons must remain capable of bringing them over threshold for contraction.”

  • The paper relies on this without support.

    The forces that generate flexibility and those that generate stability are able to coexist without interfering with each other.

    “Somehow the forces that generate flexi-bility and those that generate stability are able to coexist without interfering with each other, and together enable the remarkable ability of organisms to generate behaviors that are both coherent and adaptable.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Normalizing by the total number of incoming synapses provides a form of homeostatic synaptic scaling.

    “normalizing by the total number of incoming synapses provides a form of homeostatic synaptic scaling46.”

    From Predicting modular functions and neural coding of behavior from a synaptic wiring diagram (2024) · cites this paper as [46]

    The ‘Cell-autonomous, global synaptic scaling of excitatory synapses’ section describes compensatory changes in synaptic strength in response to activity, but does not say that dividing by the total number of incoming synapses produces such scaling. Searches for that normalization rule and for synapse-count normalization found no passage addressing it; the indexed passages provide no page numbers. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Evers study has conflicting publication years

    Minor

    The text cites the Evers study as published in 2011, but the corresponding reference lists it as published in 2010.

1 of 1

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Related

Authors
Turrigiano, G.
Affiliations
Brandeis University (US)
Corresponding author
Turrigiano, G.
ORCID
Turrigiano, G.
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2011-11-15
Volume
4
Issue
1
Pages
a005736-a005736
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a005736
PMC
PMC3249629
OpenAlex
W2115900486
Semantic Scholar
a5724cd9f8c115624f0538915997ae22b3136e77
Cited by
1,139
References
110
Citations by year
2026: 95 · 2025: 98 · 2024: 82 · 2023: 92 · 2022: 91 · 2021: 107 · 2020: 92 · 2019: 80 · 2018: 77 · 2017: 89 · 2016: 59 · 2015: 69 · 2014: 41 · 2013: 51 · 2012: 15
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
homeostatic plasticity, synaptic scaling, glutamate receptor trafficking, excitation-inhibition balance, neuronal firing rate
MeSH terms
Animals, Homeostasis, Humans, Nerve Net, Neuromuscular Junction, Neuronal Plasticity, Neurons, Synapses

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