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Cited by 189Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines

Open access
Pathania, M, Davenport, E C, Muir, J, Sheehan, D F, López-Doménech, G, Kittler, J T·2014·Translational Psychiatry
DOI 10.1038/tp.2014.16PMC PMC3966042
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Abstract

Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region,Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly,Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons.In vivo,Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.

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Written from the paper’s full text.

TL;DR

CYFIP1 is enriched at excitatory synapses and bidirectionally regulates dendritic complexity, spine maturity, spine actin dynamics, and synaptic AMPA receptor mobility. Cyfip1 haploinsufficiency in mice reduces hippocampal dendritic complexity and increases immature spines, while complete Cyfip1 deletion causes early embryonic lethality.

Key findings

  • CYFIP1 and CYFIP2 were enriched at Homer/VGLUT-positive excitatory synaptic sites compared with total dendritic processes (CYFIP1, 91.4±9.8% increase, P<0.001; CYFIP2, 85.9±12.6% increase, P<0.001).
  • CYFIP1 or CYFIP2 overexpression increased dendritic complexity and length in vitro (dendritic length: CYFIP1, 37% increase, 2876±174 μm, P<0.01; CYFIP2, 33% increase, 2787±152 μm, P<0.01; GFP, 2099±163 μm) and shifted spines toward immature forms (30% fewer stubby spines; 24% more long, thin spines; 145% more filopodia).
  • Cyfip1+/− neurons showed reduced dendritic complexity and length (15% decrease in total dendritic length, WT: 2704±96.8 μm vs Cyfip1+/−: 2298±80.2 μm, P<0.01; 20% decrease in branch points, WT: 76.7±4.1 vs Cyfip1+/−: 61.4±3.6, P<0.01), increased long, thin spines and filopodia, increased mobile F-actin, occluded NMDA-induced spine shrinkage, and increased synaptic GluA2 mobility (Din WT: 0.023 μm2 s−1 vs Cyfip1+/−: 0.034 μm2 s−1, P<0.01).
  • In vivo, Cyfip1+/− P55–60 mice had reduced CA1 dendritic complexity and a 40% increase in long, thin apical oblique spines (WT: 0.56±0.066 spines μm−1 vs Cyfip1+/−: 0.79±0.078 spines μm−1, P<0.05); complete Cyfip1 knockout was embryonic lethal, with null embryos not surviving beyond E8.5.

Methods

  • Hippocampal cultures from E16 mouse embryos (Cyfip1+/+ × Cyfip1+/− crosses) or E18 rat embryos were transfected with CYFIP1GFP, CYFIP2GFP, CYFIP1mCherry, actinGFP, DsRed, GluA2SEP, or LifeactGFP and analyzed by confocal microscopy.
  • Dendritic morphology was assessed by Sholl analysis and reconstruction; spines on 100–200 μm secondary dendrites were classified as stubby, mushroom, long and thin, or filopodia. Actin dynamics and structural plasticity were measured by FRAP and a chemical NMDA/glycine long-term depression protocol.
  • Single-molecule quantum dot imaging tracked GluA2SEP surface receptor mobility. In vivo morphology used Golgi staining of P55–60 mouse hippocampal CA1 neurons, with Neurolucida tracing; three males per condition and at least three cells per animal were analyzed.

Limitations

  • No explicit limitations section is present in the paper.
  • Evident from the text: many mechanistic conclusions rely on in vitro overexpression and Cyfip1+/− cultures, and the in vivo Golgi analysis was limited to male mice at P55–60.
  • Evident from the text: complete Cyfip1 deletion is embryonically lethal by E8.5, preventing analysis of CYFIP1-null neurons; the authors also note that CYFIP2 cannot compensate for all CYFIP1 functions and that whether CYFIP2 is a susceptibility gene remains to be explored.

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

Integrity signals

Registry

Crossref · 10.1038/tp.2014.16

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

57 of 92 cited sources checked · 8 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    Copy number variation at the 15q11.2 region is a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia and autism spectrum disorder.

    “Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD).”
    • Also stated in: § Introduction · plain
      “Copy number variations of the 15q11.2 region of the human genome are implicated in the development of neurological and neuropsychiatric conditions such as autism spectrum disorder (ASD), epilepsy, intellectual disability (ID) and schizophrenia (SCZ).1, 2, 3, 4, 5, 6, 7”
    Quote in the paperSubstantial claim4 of 7 sources checked
    • cites [1] Van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV et al. A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 960–966. source

      The indexed text reports a 15q11.2 microduplication co-segregating with autism in one family and describes the locus as a possible shared susceptibility region for ASD and schizophrenia. But it says the difference in duplication prevalence between ASD patients and controls was not statistically significant (p=0.247) and that its status as an autism risk factor remains under debate. It therefore does not establish 15q11.2 CNV as a significant risk locus for both conditions. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [2] Bittel DC, Kibiryeva N, Butler MG . Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome. Pediatrics 2006; 118: e1276–e1283. source

      The Abstract (page not available) links deletions in 15q11–q13 to Prader–Willi syndrome, a neurodevelopmental disorder, and describes behavioral differences between deletion subgroups. It does not identify 15q11.2 copy-number variation as a significant risk locus for schizophrenia or autism spectrum disorder; searches for both conditions found no supporting passage. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [3] Marini C, Cecconi A, Contini E, Pantaleo M, Metitieri T, Guarducci S et al. Clinical and genetic study of a family with a paternally inherited 15q11-q13 duplication. Am J Med Genet A 2013; 161: 1459–1464. source
    • cites [4] Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 2009; 52: 108–115. source
    • cites [5] Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      The paper reports a significant association between the 15q11.2 deletion and schizophrenia or related psychoses (Abstract; page unavailable). It also discusses autistic features in Angelman syndrome cases with larger deletions that include 15q11.2, but does not establish the 15q11.2 CNV itself as a significant risk locus for autism spectrum disorder. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [6] Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 2011; 70: 886–897. source
    • cites [7] Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372. source

      On p. 1, the paper identifies maternal duplication of 15q11–q13 as a chromosomal rearrangement associated with ASD. It does not identify CNV specifically at 15q11.2 as a significant risk locus or establish an association between that locus and schizophrenia; the schizophrenia reference on p. 4 is not locus-specific. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Copy number variation of CYFIP1 within 15q11.2 is linked to both autism spectrum disorder and schizophrenia.

    “Copy number variation of one gene within 15q11.2, coding for the cytoplasmic FMRP-interacting protein 1 (CYFIP1), has been linked to both ASD and SCZ.5,8,9”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [5] Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      The paper reports an association between a 15q11.2 deletion and schizophrenia, and identifies CYFIP1 as the gene most likely to contribute to both that phenotype and autistic features in Angelman syndrome (passages [8] and [1], section labelled Abstract; no page supplied). But the deletion spans several genes, and the autism evidence concerns features in Angelman syndrome rather than a demonstrated association between CYFIP1-specific copy-number variation and ASD. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [8] Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G et al. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012; 8: e1002521. source
    • cites [9] Tam GW, van de Lagemaat LN, Redon R, Strathdee KE, Croning DE, Malloy MP et al. Confirmed rare copy number variants implicate novel genes in schizophrenia. Biochem Soc Trans 2010; 38: 445–451. source
  • Premisecitation

    Altered levels of CYFIP1 are associated with several neurological disorders including SCZ and ASD.

    “Altered levels of CYFIP1 are associated with several neurological disorders including SCZ and ASD.4,5,10”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [4] Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 2009; 52: 108–115. source
    • cites [5] Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      The paper reports an association between a 15q11.2 deletion containing CYFIP1 and schizophrenia, and proposes CYFIP1 as the gene most likely to explain autistic features associated with related deletions (Abstract; page unavailable). It also notes reduced CYFIP1 expression in fragile X syndrome. It does not establish that altered CYFIP1 levels themselves are associated with both schizophrenia and ASD. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [10] Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 2007; 16: 1682–1698. source
  • Premisecitation

    Brief bath application of 20 μM NMDA plus 20 μM glycine induces a 15-20% spine shrinkage within 40 min, measured as a decrease in spine volume without a concomitant change in spine diameter or length.

    “Brief bath application of 20 μM NMDA plus 20 μM glycine induces a 15–20% spine shrinkage within a timeframe of 40 min, which is measured as a decrease in spine volume without a concomitant change in either spine diameter or length (Figures 4f and g; Supplementary Figures 6E and F).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Nakamura Y, Wood CL, Patton AP, Jaafari N, Henley JM, Mellor JR et al. PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity. EMBO J 2011; 30: 719–730. source

      The Results section (page unavailable) reports significant spine shrinkage after 20 μM NMDA plus 20 μM glycine, and the Methods describe a 3-minute application followed by 40 minutes before fixation. But the paper measures cross-sectional area, not volume, and does not report unchanged spine diameter or length under this treatment; its live-imaging result of 19% shrinkage is at 52 minutes, not 40. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Throughout early mouse development, CYFIP1 signalling events, probably via its core conserved actin-regulatory functions, are likely critical for gastrulation and normal patterning of embryonic structure.

    “Therefore, throughout early mouse development, CYFIP1 signalling events, probably via its core conserved actin-regulatory functions, are likely critical for gastrulation and normal patterning of embryonic structure in addition to later roles in neuronal development and plasticity.72”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [72] Liu D, Bei D, Parmar H, Matus A . Activity-regulated, cytoskeleton-associated protein (Arc) is essential for visceral endoderm organization during early embryogenesis. Mech Dev 2000; 92: 207–215. source

      Section 3.2 discusses defects in Arc-null mouse embryos, early patterning, and a possible relationship between Arc and the actin cytoskeleton. The Introduction likewise concerns Arc’s neuronal functions. A search for CYFIP1 found no passage addressing CYFIP1 signalling or its proposed role in gastrulation, so this copy cannot verify the claim attributed to it. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 27
  • The quote only partly states this claim. 1

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

    Premisecitation

    Rac1 binding results in dissociation of CYFIP1 from the WAVE regulatory complex, allowing WAVE to activate Arp2/3 and enabling de novo F-actin assembly.

    “Rac1 binding results in dissociation of CYFIP1 from the WAVE regulatory complex, allowing WAVE to activate the actin nucleator Arp2/3 and subsequently enabling de novo F-actin assembly.30,31”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48. source
    • cites [31] Chen Z, Borek D, Padrick SB, Gomez TS, Metlagel Z, Ismail AM et al. Structure and control of the actin regulatory WAVE complex. Nature 2010; 468: 533–538. source

      The ‘Activation by Rac’ section (page not provided) says Rac1 activates the WRC without disrupting the complex’s integrity, contrary to the claimed dissociation of CYFIP1 (Sra1). It proposes release of WAVE’s VCA motif instead. The Abstract supports the downstream Arp2/3-mediated actin-assembly point, but not the stated dissociation mechanism. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mice lacking other critical actin-regulatory genes such as Rac1 and the WAVE complex component Nap1 show similar developmental abnormalities, resulting in death during early embryogenesis; deletion of Rac1 and Nap1 causes death during gastrulation at E7.5 and E9, respectively.

    “Similar developmental abnormalities, resulting in death during early embryogenesis, have been observed in mice lacking other critical actin-regulatory genes such as Rac1 and the WAVE complex component Nap1. Deletion of these genes in the mouse cause death during gastrulation at E7.5 and E9, respectively.69, 70, 71”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [69] Yan C, Martinez-Quiles N, Eden S, Shibata T, Takeshima F, Shinkura R et al. WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility. EMBO J 2003; 22: 3602–3612. source

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

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [70] Migeotte I, Omelchenko T, Hall A, Anderson KV . Rac1-dependent collective cell migration is required for specification of the anterior-posterior body axis of the mouse. PLoS Biol 2010; 8: e1000442. source

      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 [71] Rakeman AS, Anderson KV . Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching. Development 2006; 133: 3075–3083. 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

  • Classified as probably not a substantial claim.

    Premisecitation

    Disruption in dendritic morphogenesis, synaptogenesis or activity-dependent remodelling produces network-wide deficits in neuronal connectivity.

    “A disruption in any of these processes produces network-wide deficits in neuronal connectivity”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [16] Kulkarni VA, Firestein BL . The dendritic tree and brain disorders. Mol Cell Neurosci 2012; 50: 10–20. source
    • cites [17] Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey KM . Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 2011; 14: 285–293. source

      The Abstract (page unavailable) says spine changes help establish and remodel circuit connectivity and may markedly affect connectivity patterns. The Conclusions and future directions (page unavailable) links disease-related spine changes to altered circuit-level connectivity. Neither passage establishes that disruption of any one of the three named processes necessarily produces network-wide deficits; the claim makes the effect more categorical and extensive than the paper does. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [18] Ebert DH, Greenberg ME . Activity-dependent neuronal signalling and autism spectrum disorder. Nature 2013; 493: 327–337. source

      The ‘Neuronal activity regulates synapses and circuits’ section says activity regulates synaptic development and plasticity, altering neural circuits. The Abstract also links disrupted activity-dependent synapse development to altered neurotransmission. But the paper does not establish that disruption of any one of the named processes necessarily produces network-wide connectivity deficits; its broader causal discussion remains qualified. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [19] Van Spronsen M, Hoogenraad CC . Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep 2010; 10: 207–214. source

      The Introduction (page not provided) says that loss of synaptic stability may disrupt neuronal circuits, supporting the general connection. It does not establish that disruption of any of the three named processes necessarily produces network-wide connectivity deficits; the claim is more categorical and specific than the source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The main role of CYFIP1 in the WAVE regulatory complex is to maintain the complex in an inhibited state until Rac1 binds CYFIP1.

    “The main role of CYFIP1 in this complex is to maintain the WAVE regulatory complex in an inhibited state until the small GTPase Rac1, once activated, binds CYFIP1.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48. source
    • cites [31] Chen Z, Borek D, Padrick SB, Gomez TS, Metlagel Z, Ismail AM et al. Structure and control of the actin regulatory WAVE complex. Nature 2010; 468: 533–538. source

      The ‘Mechanism of WRC inhibition’ section shows that Sra1/CYFIP1 helps sequester WAVE’s activity-bearing VCA motif, and ‘Activation by Rac’ identifies an Sra1 surface involved in Rac1 binding. But the paper presents release of that inhibition by Rac1 as a proposed mechanism, not a certainty, and also describes activation by kinases and phosphatidylinositols. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Changes in morphological complexity, dendritic spine number, shape and plasticity are associated with several neuropsychiatric and neurological disorders, including schizophrenia, autism spectrum disorder, intellectual disability and epilepsy.

    “changes in morphological complexity, dendritic spine number, shape and plasticity are associated with several neuropsychiatric and neurological disorders, including SCZ, ASD, ID and epilepsy.16, 17, 18, 19”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [16] Kulkarni VA, Firestein BL . The dendritic tree and brain disorders. Mol Cell Neurosci 2012; 50: 10–20. source
    • cites [17] Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey KM . Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 2011; 14: 285–293. source

      The Abstract and ‘Neuropathological studies of spine morphology’ section associate changes in spine number and morphology with schizophrenia and ASD, and the latter also notes spine alterations in disorders historically termed mental retardation. The ‘Conclusions and future directions’ section mentions epilepsy as a comorbidity of ASD, but does not establish the claimed association between epilepsy itself and changes in dendritic spines. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [18] Ebert DH, Greenberg ME . Activity-dependent neuronal signalling and autism spectrum disorder. Nature 2013; 493: 327–337. source

      The 'Synaptic proteins implicated in ASD > Shanks' section (page not supplied) links synaptic morphology and function to ASD-associated mutations, supporting the ASD portion. The paper also says that people with ASD often have intellectual disability and seizures, but it does not establish the claimed association of dendritic changes with schizophrenia, intellectual disability and epilepsy as separate disorders, or document all the specified changes in spine number, shape and plasticity. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] Van Spronsen M, Hoogenraad CC . Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep 2010; 10: 207–214. source

      The Introduction (page unavailable) links abnormal dendritic spine density and morphology and aberrant synaptic plasticity to neuropsychiatric diseases, including schizophrenia, autism, and intellectual disability. The Conclusions (page unavailable) link epilepsy to disrupted excitatory–inhibitory synaptic balance, but do not specifically associate it with the claimed changes in dendritic morphology or spines. The copy also does not clearly address changes in overall morphological complexity. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Dendritic morphogenesis, synaptogenesis and continued activity-dependent remodelling of synaptic connections are critical for the development and maintenance of functional neuronal networks.

    “Dendritic morphogenesis, synaptogenesis and continued activity-dependent remodelling of synaptic connections are critical for the development and maintenance of functional neuronal networks.11, 12, 13, 14, 15”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [11] Jan Y-N, Jan LY . Branching out: mechanisms of dendritic arborization. Nat Rev Neurosci 2010; 11: 316–328. source

      The section on dendrite morphogenesis says that neurons coordinate their dendritic fields, and the section on synaptic proteins links dendrite morphology with synaptic function (page numbers not supplied). The review thus supports the importance of dendritic development to neuronal circuitry, but it does not establish the claim about synaptogenesis and continued activity-dependent remodelling of synaptic connections. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [12] Waites CL, Craig AM, Garner CC . Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 2005; 28: 251–274. source
    • cites [13] Alvarez VA, Sabatini BL . Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci 2007; 30: 79–97. source
    • cites [14] Pozo K, Goda Y . Unraveling mechanisms of homeostatic synaptic plasticity. Neuron 2010; 66: 337–351. source

      The Introduction describes activity-dependent changes in synaptic strength and their role in maintaining network stability. The Excitatory-inhibitory balance section also notes synapse remodeling in developing networks. Our copy does not establish the claimed importance of dendritic morphogenesis or synaptogenesis for developing and maintaining functional networks. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [15] Hering H, Sheng M . Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2001; 2: 880–888. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Alterations in the regulation of actin at dendritic spines by neurodevelopmental disease-associated proteins such as DISC1, DTNBP1, SHANK3, PAK3, Oligophrenin and SRGAP2 produce deficits in synaptic plasticity and in the formation and consolidation of long-term memories.

    “Moreover, alterations in the regulation of actin at dendritic spines, by neurodevelopmental disease-associated proteins such as DISC1, DTNBP1, SHANK3, PAK3, Oligophrenin and SRGAP2, have been shown to produce deficits in both synaptic plasticity and the formation and consolidation of long-term memories.23, 24, 25, 26, 27, 28, 29”
    Quote in the paperSubstantial claim4 of 7 sources checked
    • cites [23] Kim IH, Racz B, Wang H, Burianek L, Weinberg R, Yasuda R et al. Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J Neurosci 2013; 33: 6081–6092. source

      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 [24] Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat. Neurosci 2010; 13: 327–332. source

      The Results section (“Long-term effects of DISC1 on dendritic spines”; page unavailable) reports that prolonged DISC1 knockdown reduced spine size, surface GluR1 expression and miniature excitatory postsynaptic current frequency. This supports a role for DISC1 in spine structure and synaptic function, but the paper does not show deficits in the formation or consolidation of long-term memories. Its findings do not establish the sentence’s broader claim for the other listed proteins. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [25] Ito H, Morishita R, Shinoda T, Iwamoto I, Sudo K, Okamoto K et al. Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Mol Psychiatry 2010; 15: 976–986. source
    • cites [26] Hayashi ML, Choi S-Y, Rao BS, Jung H-Y, Lee H-K, Zhang D et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron 2004; 42: 773–787. source

      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 [27] Govek E-E, Newey SE, Akerman CJ, Cross JR, Van der Veken L, Van Aelst L . The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat Neurosci 2004; 7: 364–372. source
    • cites [28] Charrier C, Joshi K, Coutinho-Budd J, Kim J-E, Lambert N, de Marchena J et al. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 2012; 149: 923–935. source
    • cites [29] Durand CM, Perroy J, Loll F, Perrais D, Fagni L, Bourgeron T et al. SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry 2012; 17: 71–84. source

      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

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

    Premisecitation

    Actin cytoskeletal dynamics have a key role in the establishment and maintenance of dendritic arborizations and spines, and are critical for structural alterations in spine shape important for cellular forms of synaptic plasticity such as long-term potentiation and long-term depression.

    “Actin cytoskeletal dynamics have a key role in the establishment and maintenance of both dendritic arborizations and spines, and are also critical for the structural alterations in spine shape important for cellular forms of synaptic plasticity, such as long-term potentiation and long-term depression.20, 21, 22, 23”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [20] Luo L . Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol 2002; 18: 601–635. source
    • cites [21] Cingolani LA, Goda Y . Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 2008; 9: 344–356. source
    • cites [22] Hotulainen P, Hoogenraad CC . Actin in dendritic spines: connecting dynamics to function. J Cell Biol 2010; 189: 619–629. 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 [23] Kim IH, Racz B, Wang H, Burianek L, Weinberg R, Yasuda R et al. Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J Neurosci 2013; 33: 6081–6092. 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

  • Classified as probably not a substantial claim.

    Premisecitation

    How both deletions and duplications affecting Cyfip1 expression produce similar neuropsychiatric phenotypes has not yet been addressed.

    “Furthermore, how both deletions and duplications affecting Cyfip1 expression produce similar neuropsychiatric phenotypes has also not yet been addressed.34,35”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [34] De Rubeis S, Bagni C . Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders. J Neurodev Disord 2011; 3: 257–269. source

      The ‘Translational control and Autism Spectrum Disorder’ section reports that both microdeletions and microduplications in the region containing CYFIP1 co-segregate with cognitive disabilities and ASD. ‘Future perspectives’ says little is known about FMRP–CYFIP1 interaction networks, but does not specifically say that how deletions and duplications produce similar phenotypes remains unaddressed. Page numbers are unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [35] Bozdagi O, Sakurai T, Dorr N, Pilorge M, Takahashi N, Buxbaum JD . Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice. Dawson TM, editor. PLoS One 2012; 7: e42422. source

      The Discussion (page not provided) cites evidence linking both 15q11.2 deletions and duplications to psychiatric phenotypes, but its functional analysis examines reduced Cyfip1 expression in heterozygous mice. It does not state that the mechanism by which both changes produce similar phenotypes had not yet been addressed. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Rare complete gene knockouts in humans have a significant role in ASD and major mental illness.

    “Recent work has highlighted that rare complete gene knockouts in humans have a significant role in ASD and major mental illness.68”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [68] Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, MacArthur DG et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 2013; 77: 235–242. source

      The Results section, “Enrichment of Rare Complete Knockouts in ASD,” reports roughly two-fold enrichment in ASD cases and estimates a 3% contribution to ASD. The paper does not establish a significant role for these knockouts in major mental illness more broadly; a search for that claim found no supporting passage. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    CYFIP1 couples local actin polymerization to membrane budding at subcellular compartments such as the trans-Golgi network.

    “CYFIP1 has been previously shown to couple local actin polymerization to membrane budding at subcellular compartments such as the trans-Golgi network.33,62”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [33] Anitei M, Stange C, Parshina I, Baust T, Schenck A, Raposo G et al. Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-AP-1-coated carrier biogenesis at the TGN. Nat Cell Biol 2010; 12: 330–340. source
    • cites [62] Castets M, Schaeffer C, Bechara E, Schenck A, Khandjian EW, Luche S et al. FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts. Hum Mol Genet 2005; 14: 835–844. source

      The Results section, “FMRP interacting proteins relocalize to actin ring areas in PDGF-stimulated fibroblasts” (page not available), reports that CYFIP1 relocates to actin ring areas. It does not show that CYFIP1 couples actin polymerization to membrane budding or place that process at the trans-Golgi network. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Microdeletion at 15q11.2 renders people haploinsufficient for Cyfip1 and is associated with autism spectrum disorder and schizophrenia.

    “Microdeletion at 15q11.2 renders people haploinsufficient for Cyfip1 and is associated with ASD and SCZ.4,6,7”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [4] Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet 2009; 52: 108–115. source
    • cites [6] Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 2011; 70: 886–897. source
    • cites [7] Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372. source

      The introduction (p. 1) links copy-number variation to ASD and mentions maternal duplication of 15q11–q13, but not a 15q11.2 microdeletion. Searches for CYFIP1, 15q11.2 deletion, and schizophrenia found no passage establishing CYFIP1 haploinsufficiency or the claimed association with both disorders. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

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

    Premisecitation

    CYFIP1 translocates between the FMRP-containing protein synthesis machinery and the actin-regulatory complex.

    “This is in agreement with a recent study showing that CYFIP1 translocates between the FMRP-containing protein synthesis machinery and the actin-regulatory complex, and that disrupting CYFIP1's interaction with members of either complex negatively impacted spine maturation in neurons.34”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] De Rubeis S, Bagni C . Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders. J Neurodev Disord 2011; 3: 257–269. source

      The section on the FMRP-CYFIP1-eIF4E complex (page unavailable) places CYFIP1 in both an FMRP-associated translation complex and WAVE-associated actin-regulatory machinery. It describes release from eIF4E after synaptic stimulation, but does not say CYFIP1 translocates between the two complexes. The cited sentence’s additional claim about disrupted interactions impairing spine maturation is also not established by these passages. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    CYFIP1 couples actin dynamics to other cellular processes, such as carrier vesicle biogenesis in the trans-Golgi network, and, via interactions with FMRP, regulates synaptic mRNA translation in an activity-dependent manner.

    “Furthermore, CYFIP1 couples actin dynamics to other cellular processes, such as carrier vesicle biogenesis in the trans-Golgi network, and, via interactions with the FRMP (Fragile X mental retardation protein), regulates synaptic mRNA translation in an activity-dependent manner.32,33”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [32] Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 2008; 134: 1042–1054. source

      The Discussion (p. 8) identifies CYFIP1 as a component of the actin-polymerization WAVE complex, and the synapse experiments (p. 8) support activity-dependent regulation of translation through the FMRP–CYFIP1 complex. Our copy does not support the further claim that CYFIP1 couples actin dynamics to carrier vesicle biogenesis in the trans-Golgi network. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [33] Anitei M, Stange C, Parshina I, Baust T, Schenck A, Raposo G et al. Protein complexes containing CYFIP/Sra/PIR121 coordinate Arf1 and Rac1 signalling during clathrin-AP-1-coated carrier biogenesis at the TGN. Nat Cell Biol 2010; 12: 330–340. source

      The Results (page not specified) show that CYFIP1 depletion reduces formation of TGN-derived carriers, and the Discussion describes CYFIP-containing complexes coordinating actin polymerization with carrier biogenesis. The Discussion also links CYFIP1 to FMRP, but the paper does not say that CYFIP1 regulates synaptic mRNA translation in an activity-dependent manner. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Several other proteins known to signal via actin-regulatory pathways, including VCP/neurofibromin, NESH/Abi-3 and Cofilin, drive similar effects on spine structure when either up- or downregulated.

    “As we observe an increase in immature spines upon CYFIP1 overexpression or haploinsufficiency in vitro, it is interesting to note that several other proteins known to signal via actin-regulatory pathways have been shown to drive similar effects on spine structure when either up- or downregulated, including VCP/neurofibromin, NESH/Abi-3 and Cofilin.47,48,57,64, 65, 66, 67”
    Quote in the paperNot a substantial claim6 of 7 sources checked
    • cites [47] Wear MA, Schafer DA, Cooper JA . Actin dynamics: assembly and disassembly of actin networks. Curr Biol 2013; 10: R891–R895. source

      The paper’s “Future directions” section describes ADF/cofilin as acting through actin-filament severing, supporting its connection to actin regulation. It does not report effects of cofilin up- or downregulation on dendritic spines, or address VCP/neurofibromin or NESH/Abi-3. No page number is available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [48] Condeelis J . How is actin polymerization nucleated in vivo? Trends Cell Biol 2001; 11: 288–293. source
    • cites [57] Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K . Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 2003; 38: 447–460. source

      The Discussion (page unavailable) links ADF/cofilin to actin dynamics and proposes that its phosphorylation may regulate spine morphology. It also reports abnormal spine morphology in LIMK-1 knockout mice, but does not show that up- or downregulating cofilin itself produces the cited increase in immature spines. The other named proteins are not findings attributed specifically to this paper. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [64] Bae J, Sung BH, Cho IH, Kim S-M, Song WK . NESH regulates dendritic spine morphology and synapse formation. PLoS One 2012; 7: e34677. source
    • cites [65] Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M et al. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 2002; 35: 121–133. source

      The Results report altered spine shape in LIMK-1 knockout mice, and the Discussion links LIMK-1 to cofilin phosphorylation and actin dynamics. This supports a cofilin-related pathway affecting spine structure, but the study did not up- or downregulate cofilin itself; it reports unchanged total cofilin. It does not address VCP/neurofibromin or NESH/Abi-3. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [66] Hotulainen P, Llano O, Smirnov S, Tanhuanpää K, Faix J, Rivera C et al. Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J Cell Biol 2009; 185: 323–339. source
    • cites [67] Wang H-F, Shih Y-T, Chen C-Y, Chao H-W, Lee M-J, Hsueh Y-P . Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J Clin Invest 2011; 121: 4820–4837. source

      The Introduction (p. 1) links neurofibromin to actin regulation, and the results (pp. 5–7, 12) show that VCP knockdown and overexpression of a VCP domain reduce dendritic spine density. But the paper does not report the cited increase in immature spines: it says VCP knockdown did not change spine length or head width (p. 6), and wild-type VCP overexpression did not impair spine density (p. 12). This verdict concerns VCP/neurofibromin, not the other proteins named in the multi-citation sentence. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    AMPA receptors mediate fast excitatory synaptic transmission within the central nervous system.

    “AMPA receptors mediate fast excitatory synaptic transmission within the CNS.44,45”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [44] Shepherd JD, Huganir RL . The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 2007; 23: 613–643. source
    • cites [45] Anggono V, Huganir RL . Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 2012; 22: 461–469. source

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

    Premisecitation

    A role for CYFIP1 in the regulation of Rac1-dependent F-actin assembly in Drosophila NMJ presynaptic terminals has been demonstrated, where it is important for synaptogenesis and presynaptic quantal content.

    “A role for CYFIP1 in the regulation of Rac1-dependent F-actin assembly in Drosophila NMJ presynaptic terminals was also recently demonstrated, where it was shown to be important for synaptogenesis and presynaptic quantal content.51,52”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [51] Zhao L, Wang D, Wang Q, Rodal AA, Zhang YQ . Drosophila cyfip regulates synaptic development and endocytosis by suppressing filamentous actin assembly. PLoS Genet 2013; 9: e1003450. source

      The Abstract and Results report altered F-actin assembly and synaptic development at Drosophila NMJs, along with reduced quantal content in cyfip mutants. But the Introduction says the Rac1-to-WAVE mechanism had been demonstrated only in vitro; this paper does not demonstrate that the NMJ effects are Rac1-dependent. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Schenck A, Bardoni B, Langmann C, Harden N, Mandel JL, Giangrande A . CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 2003; 38: 887–898. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Actin dynamics in spines have a major role in coordinating the delivery and removal of AMPA receptors and the strength of synapses.

    “Actin dynamics in spines have a major role in coordinating the delivery and removal of AMPA receptors and the strength of synapses.45”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Anggono V, Huganir RL . Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 2012; 22: 461–469. source

      The Protein 4.1N section says the actin cytoskeleton immobilizes glutamate receptors at synapses and is important for synaptic plasticity. The PICK1 section describes a possible role for actin polymerization in AMPA receptor internalization. The paper does not establish the broader claim that actin dynamics in spines coordinate both receptor delivery and removal. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The surface mobility of neurotransmitter receptors is dynamically regulated to control synaptic activity and is a key component underlying plasticity at nerve terminals.

    “The surface mobility of neurotransmitter receptors is dynamically regulated to control synaptic activity and is emerging as another key component underlying plasticity at nerve terminals.40,53,54”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [40] Muir J, Arancibia-Carcamo IL, MacAskill AF, Smith KR, Griffin LD, Kittler JT . NMDA receptors regulate GABAA receptor lateral mobility and clustering at inhibitory synapses through serine 327 on the γ2 subunit. Proc Natl Acad Sci USA 2010; 107: 16679–16684. source

      The Introduction says receptor movement into and out of synapses is an emerging mechanism for regulating synaptic strength, and the Discussion reports activity-dependent changes in GABA_A receptor mobility. The paper links this mechanism to inhibitory synaptic plasticity, but studies receptors at inhibitory synapses, not plasticity at nerve terminals specifically. No page numbers are available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [53] Triller A, Choquet D . New concepts in synaptic biology derived from single-molecule imaging. Neuron 2008; 59: 359–374. source

      The passages under “Concepts that Have Emerged from Single-Molecule Imaging in Synaptic Biology” report that receptor movements are modulated by neuronal activity. The passage on fast synaptic transmission says AMPA-receptor lateral diffusion affects synaptic signaling and recovery from postsynaptic depression. These support a role in synaptic activity and plasticity, but they concern postsynaptic receptors, not plasticity specifically at nerve terminals. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [54] Pinaud F, Clarke S, Sittner A, Dahan M . Probing cellular events, one quantum dot at a time. Nat Methods 2010; 7: 275–285. source

  • May combine two claims.

    Findingown data

    CYFIP1 overexpression decreases spine diameter but increases spine volume overall due to increased spine length.

    “CYFIP1 overexpression also significantly decreased spine diameter, whereas spine volume showed an overall increase due to the dominating effect of the increase in spine length (Supplementary Figures 6C and D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cyfip1 haploinsufficient neurons have reduced total dendritic length and number of branch points compared with wild-type.

    “Furthermore, both total dendritic length and the total number of branch points were reduced in Cyfip1+/− neurons compared with control (15% decrease in total dendritic length in Cyfip1+/− neurons, WT: 2704±96.8 μm, Cyfip1+/−: 2298±80.2 μm, P<0.01; 20% decrease in number of branch points in Cyfip1+/− neurons, WT: 76.7±4.1, Cyfip1+/−: 61.4±3.6, P<0.01; Figures 3d and e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CYFIP1 overexpression decreases stubby spine number and increases long, thin spine and filopodia numbers.

    “CYFIP1 overexpressors had significantly fewer stubby spines (30% decrease in stubby spines, DsRed+actinGFP: 0.32±0.01 spines μm−1, CYFIP1mCherry+actinGFP: 0.24±0.01 spines μm−1, P<0.01) and increased numbers of long, thin spines and filopodia (24% increase in long, thin spines, DsRed+actinGFP: 0.14±0.01 spines μm−1, CYFIP1mCherry+actinGFP: 0.17±0.01 spines μm−1, P<0.05; 145% increase in filopodia,”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cyfip1 knockout embryos are detectable until embryonic day 8.5 and are significantly reduced in size and display delayed development compared with heterozygous or wild-type counterparts.

    “However, fertilized KO oocytes from Cyfip1+/− × Cyfip1+/− crosses did persist up to the blastocyst stage in vitro (not shown), and in pregnant dams, they were detectable until embryonic day 8.5 (E8.5) postcoitum (Supplementary Table 1). At this stage, Cyfip1 KO embryos were significantly reduced in size and displayed delayed development compared with their heterozygous (Cyfip1+/−) or wild-type (WT”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpression of CYFIP1 or CYFIP2 increases total dendritic length and total number of branch points per cell.

    “In addition, total dendritic length and the total number of branch points per cell were also increased in the CYFIP1 and CYFIP2 overexpressors (dendritic length: CYFIP1, 37% increase, 2876±174 μm, P<0.01; CYFIP2, 33% increase, 2787±152 μm, P<0.01; GFP, 2099±163 μm; branch points: CYFIP1, 48% increase, 66.5±7.0, P<0.05; CYFIP2, 101% increase, 90.1±5.6, P<0.001; GFP 44.8±7.7; Figures 2d and e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cyfip1 knockout embryos show complete developmental failure with reduced body elongation and patterning.

    “Further examination revealed complete developmental failure resulting in reduced body elongation and patterning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cyfip1 heterozygous animals are viable until adulthood, fertile, and show no gross morphological abnormalities in brain structure compared with wild-type.

    “Cyfip1+/− heterozygous animals on the other hand, were viable until adulthood, were fertile and did not show any gross morphological abnormalities in brain structure when compared with WT (Supplementary Figure 3H).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    CYFIP1 and CYFIP2 are highly enriched at excitatory synapses in dendritic spines.

    “CYFIP1 is highly enriched at synapses”
    • Also stated in: § CYFIP1 and CYFIP2 are enriched at excitatory synapses · hedged
      “CYFIP1GFP and CYFIP2GFP exhibited a nonuniform distribution appearing to be selectively targeted to punctate clusters in spines and along dendrites”
    • Also stated in: § CYFIP1 and CYFIP2 are enriched at excitatory synapses · plain
      “endogenous CYFIP1 was also highly enriched at excitatory synapses and co-localized with the excitatory marker PSD-95”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In vivo, Cyfip1 heterozygous animals exhibit deficits in dendritic complexity and an altered ratio of immature-to-mature spines in hippocampal CA1 neurons.

    “In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cyfip1+/− spines show no change in spine volume following NMDA application and remain unchanged from basally low levels.

    “Cyfip1+/− spines showed no change in spine volume following NMDA application and spine volume remained unchanged from its basally low levels (16% decrease in WT spine volume following NMDA treatment, no change in Cyfip1+/− spine volume following NMDA treatment, WT saline: 0.30±0.003 μm3, WT NMDA: 0.25±0.001 μm3, Cyfip1+/− saline: 0.26±0.001 μm3, Cyfip1+/− NMDA: 0.26±0.002 μm3, P<0.0001; Figures 4f”
    Quote in the paperSubstantial claim

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

    Findingown data

    CYFIP2 overexpression drives increased dendritogenesis.

    “Intriguingly, we also observed CYFIP2 to be enriched in dendritic spines and its overexpression could drive increased dendritogenesis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    CYFIP1 is a critical modulator of cellular actin dynamics as part of the WAVE regulatory complex.

    “One critical modulator of cellular actin dynamics is the ubiquitous heteropentameric WAVE regulatory complex consisting of the proteins WAVE, Abi, Nap1, HSPC300 and CYFIP1 (also known as SRA-1) or CYFIP2.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48. source

  • May combine two claims.

    Interpretationown data

    CYFIP1 mediates structural reorganization during synaptic plasticity, possibly through dynamic regulation of the local actin cytoskeleton in spines.

    “These data reveal a role for CYFIP1 in mediating structural reorganization during synaptic plasticity, possibly through dynamic regulation of the local actin cytoskeleton in spines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    When CYFIP1 levels are reduced, F-actin assembly is basally overactive and cannot induce further spine remodelling in response to NMDA.

    “We observe that NMDA receptor-induced spine remodelling no longer occurs in Cyfip1+/− neurons, suggesting that when CYFIP1 levels are reduced, F-actin assembly is basally overactive and cannot induce further spine remodelling in response to NMDA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Cyfip1 haploinsufficiency results in decreased dendritic complexity and produces alterations in spine morphology.

    “These experiments demonstrate that Cyfip1 haploinsufficiency results in decreased dendritic complexity and produces alterations in spine morphology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CYFIP1 expression levels are important for dendritic arborization and neuronal morphological complexity.

    “Here we demonstrate that CYFIP1 expression levels are important for dendritic arborization and neuronal morphological complexity.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Spine classification was entirely automated until the final step where errors in classification were removed.

    “Classification was entirely automated until the final step where errors in classification were removed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines

    CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

    “The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Three males were analysed for each condition with a minimum of three cells traced per animal.

    “Three males were analysed for each condition with a minimum of three cells traced per animal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The precise tuning of CYFIP1 expression levels may be crucial for stabilising synaptic contacts, and skewing its levels above or below a critical threshold may force spines into a structurally unstable state.

    “Thus, the precise tuning of CYFIP1 expression levels may be crucial for stabilising synaptic contacts, and skewing its levels above or below a critical threshold may force spines into a structurally unstable state.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    When using animals from separate litters, each genotype was equally represented from each litter.

    “When using animals from separate litters, each genotype was equally represented from each litter.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Dysregulation of CYFIP1 expression levels leads to pathological changes in central nervous system maturation and neuronal connectivity, which may contribute to the development of neurological symptoms seen in autism spectrum disorder and schizophrenia.

    “In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    CYFIP1 functions as a key, conserved regulator of actin nucleation in cells.

    “In this way, CYFIP1 functions as a key, conserved regulator of actin nucleation in cells.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Takenawa T, Suetsugu S . The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 2007; 8: 37–48. source

  • May combine two claims.

    Interpretationreasoning

    CYFIP1 expression levels appear to be critical for the maturation of dendritic spines and may be important for regulating the subsynaptic cytoskeletal architecture essential for the stabilization of postsynaptic AMPA receptors.

    “Consequently, CYFIP1 expression levels appear to be critical not just for the maturation of dendritic spines but may also be important for regulating the subsynaptic cytoskeletal architecture essential for the stabilization of postsynaptic AMPA receptors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fine-tuning of actin turnover is an important regulator of synaptic glutamate receptor mobility.

  • May combine two claims.

    Interpretationown data

    The results support a critical role for CYFIP1 in development, dendritic morphogenesis and synaptic connectivity and support the idea that dysregulated CYFIP1 mediates the molecular aetiology of 15q11.2 copy number variation-associated neuropsychiatric conditions such as autism spectrum disorder, schizophrenia and epilepsy.

    “Our results support a critical role for CYFIP1 in development, dendritic morphogenesis and synaptic connectivity and provide further support for the idea that dysregulated CYFIP1 mediates the molecular aetiology of 15q11.2 Copy number variation-associated neuropsychiatric conditions such as ASD, SCZ and epilepsy.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Changes in the structure and function of excitatory synapses, and alterations in the local versus long-range dendritic connectivity of neurons, have both been associated with the development of neuropsychiatric conditions involving imbalances of excitation and inhibition, such as ASD and SCZ.

    “Changes in the structure and function of excitatory synapses, and alterations in the local versus long-range dendritic connectivity of neurons, have both been associated with the development of neuropsychiatric conditions involving imbalances of excitation and inhibition, such as ASD and SCZ.73,74”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] Casanova MF, Buxhoeveden DP, Switala AE, Roy E . Minicolumnar pathology in autism. Neurology 2002; 58: 428–432. source
    • cites [74] Rubenstein JL, Merzenich MM . Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003; 2: 255–267. source
45 of 45

  • The paper relies on this without support.

    The exact role of CYFIP1 in normal nervous system function and development, and the consequences of its dysregulation, remain poorly understood.

    “However, the exact role that CYFIP1 has in normal nervous system function and development, and the consequences of its dysregulation, remain poorly understood.”

  • The paper relies on this without support.

    Very little is known about CYFIP1's role in establishing or maintaining neuronal connectivity, specifically its involvement in the regulation of dendritic morphology, synaptic structural plasticity and neurotransmitter receptor mobility.

    “However, still very little is known about CYFIP1's role in establishing or maintaining neuronal connectivity, specifically its involvement in the regulation of dendritic morphology, synaptic structural plasticity and neurotransmitter receptor mobility.”

  • The paper relies on this without support.

    It remains unclear what role CYFIP1 has in the establishment or maintenance of neuronal connectivity in the mammalian CNS, and how changes in its expression contribute to neurological dysfunction.

    “However, it remains unclear what role CYFIP1 has in the establishment or maintenance of neuronal connectivity in the mammalian CNS, and how changes in its expression contribute to neurological dysfunction.”

  • The paper relies on this without support.

    Fine-tuning of actin turnover is an important regulator of synaptic glutamate receptor mobility.

    “This fine-tuning of actin turnover has previously been demonstrated to be an important regulator of synaptic glutamate receptor mobility.”

  • The paper relies on this without support.

    Deficits in dendritic complexity and spine morphology in Cyfip1+/− mice are relevant to SCZ and ASD in humans.

    “Furthermore, modelling SCZ- and ASD-associated Cyfip1 haploinsufficiency in mice produces deficits in dendritic complexity and spine morphology in hippocampal pyramidal neurons in vivo.”
5 of 5

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?

  • CYFIP1 and 2 are enriched in the dendritic spines of excitatory synapses and are involved in the maintenance of dendritic complexity and dendritic spines.

    “CYFIP1 and 2 are enriched in the dendritic spines of excitatory synapses and are involved in the maintenance of dendritic complexity and dendritic spines65,66.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [65]

    The Results section, “CYFIP1 and CYFIP2 are enriched at excitatory synapses” (page unavailable), reports enrichment of both proteins in dendritic spines at excitatory synapses. The Introduction reports that overexpressing either protein increases dendritic complexity and alters spine morphology, but the evidence that reduced expression impairs maintenance of complexity and mature spines concerns CYFIP1 only; it does not establish the same maintenance role for CYFIP2. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The complexity of dendritic arborization is profoundly reduced compared with the reduced arborization of 14 DIV Cyfip1-depleted neurons shown by other authors, where higher residual expression of Cyfip1 is present.

    “The complexity of dendritic arborization is here profoundly reduced if compared with the reduced arborization of 14 DIV Cyfip1-depleted neurons as shown by other authors, where higher residual expression of Cyfip1 is present (Pathania et al., 2014).”

    From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Pathania et al., 2014

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.

  • Basal spine volume is described as both unchanged and low

    Minor

    One results section says Cyfip1 haploinsufficiency did not change spine volume, while a later section describes its basal spine volume as low and reports a lower saline-condition mean than WT. The text does not reconcile these descriptions.

1 of 1

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Authors
Pathania, M., Davenport, E. C., Muir, J., Sheehan, D. F., López-Doménech, G., & Kittler, J. T.
Affiliations
University College London (GB)
Corresponding author
Kittler, J T
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2014-03-25
Volume
4
Issue
3
Pages
e374-e374
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2014.16
PMC
PMC3966042
OpenAlex
W2031684016
Semantic Scholar
b3330cd38a232049b3cf5e69b8201cd7d3a641f9
Cited by
189
References
75
Citations by year
2026: 4 · 2025: 11 · 2024: 9 · 2023: 16 · 2022: 8 · 2021: 18 · 2020: 21 · 2019: 24 · 2018: 20 · 2017: 16 · 2016: 18 · 2015: 20 · 2014: 4
FWCI
7.81
Type
journal article
Language
en
Update notices
erratum (2014-08-05)
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • University College London
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
CYFIP1, autism spectrum disorder, schizophrenia, dendritic complexity, dendritic spines, spine maturation, actin dynamics, GluA2, haploinsufficiency, synaptic plasticity, CA1 pyramidal neurons, neuronal connectivity
MeSH terms
Animals, Dendrites, Embryo, Mammalian, Male, Nerve Tissue Proteins, Adaptor Proteins, Signal Transducing, Mice, Rats, CA1 Region, Hippocampal, Haploinsufficiency

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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Statistics and arithmetic are recomputed, not judged.

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