The DOI matches its Crossref record, with a small difference in title or year; 66 of the 66 references it cites were found in a registry or an index; 35 of the 59 sources its claims cite were checked for support.
Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function.
Open accessAbstract
Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.
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TL;DR
Dock4 knockout mice display autism-like social, vocalization, anxiety, and learning deficits, with reduced hippocampal excitatory synaptic transmission and AMPA/NMDA receptor content. Restoring Rac1 activity or NMDA receptor function in hippocampal CA1 rescues social novelty preference, implicating a Dock4-Rac1-dependent pathway in social behavior.
Key findings
- Dock4 KO mice showed impaired social novelty preference, more isolation-induced pup calls at postnatal days 3, 6, 9, and 12, longer total call duration, elevated anxiety, and perturbed object/spatial learning; conditional Dock4 deletion in hippocampal CA1 recapitulated the social preference deficit.
- In CA1 pyramidal neurons, KO mice had smaller mEPSC amplitude, unchanged mIPSCs, a substantially smaller E/I ratio, reduced AMPAR- and NMDAR-mediated EPSCs with a more prominent NMDAR reduction, a lowered NMDAR/AMPAR ratio, weaker ifenprodil blockade of NMDAR-EPSCs, and significantly reduced LTP.
- KO hippocampus showed decreased dendritic spines in CA1 and dentate gyrus and reduced synaptic expression of GluA2, GluN1, GluN2A, and GluN2B; global expression of these subunits was still reduced by 10%–30%, while mRNA levels were unaltered.
- Dock4 deficiency reduced active Rac1 and global protein synthesis; Rac1 overexpression restored protein synthesis and receptor subunit levels in vitro, rescued mEPSC and LTP in KO neurons, and corrected social novelty preference in vivo. D-cycloserine rapidly restored social novelty preference in KO mice, but the effect diminished by 7 days; the AMPAR positive allosteric modulator PF-4774857 had no effect.
Methods
- Generated whole-body Dock4 KO mice via Cre-LoxP recombination and used conditional deletion by AAV-Cre delivery into hippocampal CA1 of Dock4 fl/fl mice.
- Behavioral analyses used Dock4 KO, HET, and WT littermates of both genders aged 3–6 months, except pup-retrieval assays used virgin females; tests included three-chamber social approach/novelty, ultrasonic vocalizations, elevated zero-maze, novel object recognition, Y-maze, Morris water-maze, nesting, and pup retrieval.
- Synaptic function was assessed by whole-cell electrophysiology in hippocampal CA1 pyramidal neurons; protein expression and synthesis were measured by Western blotting, puromycin labeling, Rac1 activity assays, lentiviral Rac1 expression, and pharmacological treatments including DCS and PF-4774857.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: findings are based on mouse models and cultured neurons, with no human tissue or human behavioral validation reported.
- Evident from the text: some phenotypes were sex-specific or based on small subgroups; a small population of female HET (1.7%) and KO (9.1%) mice showed stereotyped behavior and was excluded from subsequent studies, and DCS rescue of social novelty preference diminished by 7 days after treatment.
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Claims the paper makes
65 Own result · 26 Own interpretation · 10 Partly supported · 7 Supported · 6 No full text of the sources · 5 Own method · 2 Supported so far · 1 Sources not found · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Supporting this notion, restoration of normal activity of Rac1 or its downstream effectors was demonstrated as a successful approach for correcting autism-like behaviors and synaptic abnormalities 12–15.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Partly supportedcites [12] Dolan BM, Duron SG, Campbell DA, Vollrath B, Shankaranarayana Rao BS, Ko HY, et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc Natl Acad Sci USA. 2013;110:5671–6. sourceExperimental — accuracy not yet measured
The Discussion reports that the PAK inhibitor FRAX486 reversed abnormal spine density and ameliorated autism-like behaviors in Fmr1 KO mice; the paper identifies PAK as downstream of Rac1. It does not demonstrate restoration of normal Rac1 activity, or establish that PAK activity itself was restored to a normal level. The demonstrated correction is limited to the mouse model studied. (LLM, conf=0.84)
- Supportedcites [13] Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like deficits in shank3-deficient mice are rescued by targeting actin regulators. Cell Rep. 2015;11:1400–13. source
The Results report that activating Rac1 rescued autism-like social deficits and increased synaptic NMDAR responses in Shank3-deficient mice. The Discussion also reports that inhibiting cofilin, a downstream component of the pathway, rescued social and repetitive behaviors and restored NMDAR function. The demonstrated correction is in mice, not humans. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [14] Li J, Chai A, Wang L, Ma Y, Wu Z, Yu H, et al. Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior. Proc Natl Acad Sci USA. 2015;112:E6964–72. source
- Not checked — no full text of the sourcecites [15] Martinez LA, Tejada-Simon MV. Pharmacological rescue of hippocampal fear learning deficits in fragile X syndrome. Mol Neurobiol. 2017;55:5951–61. source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Dock4, a member of the Dock (dedicator of cytokinesis) family, is an atypical Rac1 GEF linked to ASD and other neuropsychiatric disorders 17.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Supportedcites [17] Shi L. Dock protein family in brain development and neurological disease. Commun Integr Biol. 2013;6:e26839. source
The Dock-A and Dock-B section states that the gene encoding Dock4 is associated with autism, dyslexia, and schizophrenia, supporting the claimed link to ASD and other neuropsychiatric disorders. The same section describes Dock4-dependent Rac1 activation; no page number is provided in our copy. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Rac1 has been identified as a converging factor downstream of numerous proteins encoded by high-risk ASD genes, such as SHANK 4–6, FMR1 (fragile X mental retardation-1) 7, 8, NRXN 9, and AUTS2 10.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Supportedcites [4] Duffney LJ, Wei J, Cheng J, Liu W, Smith KR, Kittler JT, et al. Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J Neurosci. 2013;33:15767–78. source
The Results section reports that active Rac1 blocked the effect of Shank3 knockdown and concludes that Rac1 is required for Shank3 regulation of NMDA receptors. This supports the SHANK example attributed to this paper; the other genes have separate citations. Page numbers are unavailable in our copy. (LLM, conf=0.90)
- Partly supportedcites [5] Sarowar T, Grabrucker AM. Actin-dependent alterations of dendritic spine morphology in shankopathies. Neural Plast. 2016;2016:8051861. sourceExperimental — accuracy not yet measured
Section 5 describes SHANK3 interactions that regulate Rac1 and reports reduced Rac1 activity in Shank3-knockout mice, supporting the SHANK example. But section 4 calls FMRP an indirect downstream effector of Rac1—the reverse of the claimed direction—and the cited passages do not establish Rac1 as downstream of NRXN or AUTS2. The paper therefore supports part of the proposed convergence, not the full claim. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [6] Monteiro P, Feng G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci. 2017;18:147–57. source
- Supportedcites [7] Pyronneau A, He Q, Hwang JY, Porch M, Contractor A, Zukin RS. Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome. Sci Signal. 2017;10:eaan0852. source
The citation to this paper is attached to the FMR1 example, not to the other listed genes. The Results report increased Rac1 activity in Fmr1 knockout mice, and the Discussion describes FMRP as regulating cofilin through Rac1-PAK1 signaling. No page number is available in our copy. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [8] Martinez LA, Tejada-Simon MV. Increased training intensity induces proper membrane localization of actin remodeling proteins in the hippocampus preventing cognitive deficits: implications for fragile X syndrome. Mol Neurobiol. 2017;55:4529–42. source
- Supportedcites [9] Rui M, Qian J, Liu L, Cai Y, Lv H, Han J, et al. The neuronal protein Neurexin directly interacts with the Scribble-Pix complex to stimulate F-actin assembly for synaptic vesicle clustering. J Biol Chem. 2017;292:14334–48. source
The Results section reports reduced activated Rac1 in dnrx mutant flies and after DNRX knockdown, supporting the NRXN example to which this citation is attached. The Discussion also describes Rac1 as a proposed converging node linked to ASD and notes defective Rac1 activation in multiple autism-related gene mutations. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For instance, several microdeletions lead to loss of various lengths of the C-terminal portion of Dock4 protein 19, 21, 26, which is responsible for its Rac1-activating ability 27.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Partly supportedcites [19] Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, et al. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry. 2010;68:320–8. sourceExperimental — accuracy not yet measured
The Results report distinct DOCK4 deletions: a 594-kb IMMP2L–DOCK4 deletion and a 132-kb deletion of DOCK4 exons 38–52. They do not establish that these deletions produce proteins missing different lengths of the C-terminal portion; for the 594-kb deletion, the reported fusion transcript is likely subject to nonsense-mediated decay. The Rac1-activation clause has a separate citation in the citing sentence, although this paper’s Discussion does describe DOCK4 as a Rac1-activating factor. Page numbers were not available in our copy. (LLM, conf=0.82)
- Could not verifycites [21] Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21. sourceExperimental — accuracy not yet measured
Citation 26 is attached to the claim about microdeletions removing portions of Dock4’s C-terminus; the Rac1-activating function is separately cited to reference 27. The supplied Results and Discussion passages discuss de novo coding mutations generally, but neither they nor searches for “Dock4” and “DOCK4 microdeletions C-terminal portion” yielded a passage addressing those deletions. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [26] Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y, et al. Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep. 2018;24:2838–56. source
- Not checked — no full text of the sourcecites [27] Xiao Y, Peng Y, Wan J, Tang G, Chen Y, Tang J, et al. The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. J Biol Chem. 2013;288:20034–45. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Recent studies have identified a number of DOCK4 variations associated with ASD, including both single nucleotide variations (SNVs) and chromosome microdeletions or duplications (Supplementary Table 1) 18–26.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Partly supportedcites [18] Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I, et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry. 2010;15:954–68. sourceExperimental — accuracy not yet measured
The Discussion reports a replicated association for the DOCK4 SNP rs2217262 and suggests that a DOCK4 deletion may influence ASD susceptibility. The Results describe a duplication involving DOCK4, but the Discussion says duplications may not be damaging; this paper does not establish a duplication associated with ASD. (LLM, conf=0.86)
- Supportedcites [19] Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, et al. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry. 2010;68:320–8. source
The Abstract (Conclusions; page not supplied) reports SNPs within DOCK4 that may index autism susceptibility and a DOCK4-disrupting deletion transmitted to an affected sibling pair. The Results (page not supplied) also identify a DOCK4 duplication previously reported in an ASD family. Together, these passages support the claim about single-nucleotide and copy-number variations associated with ASD. (LLM, conf=0.89)
- Partly supportedcites [20] Liang S, Wang XL, Zou MY, Wang H, Zhou X, Sun CH, et al. Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population. J Zhejiang Univ Sci B. 2014;15:264–71. sourceExperimental — accuracy not yet measured
The Discussion reports an association between the DOCK4 SNP rs2217262 and autism, and describes genomic disruption of DOCK4 in relation to autism. The References identify a study of rare DOCK4 deletions, but our copy does not identify DOCK4 duplications associated with ASD. The claim’s duplication component is therefore unsupported by this source. (LLM, conf=0.86)
- Could not verifycites [21] Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21. sourceExperimental — accuracy not yet measured
The Introduction and Results discuss de novo coding variants and copy-number variation in ASD generally, but no passage identifies DOCK4 variants or links DOCK4 microdeletions or duplications to ASD. Searches for DOCK4 and for the specific variant types did not locate that gene in our copy. (LLM, conf=0.76)
- Could not verifycites [22] Toma C, Torrico B, Hervas A, Valdes-Mas R, Tristan-Noguero A, Padillo V, et al. Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol Psychiatry. 2014;19:784–90. sourceExperimental — accuracy not yet measured
The Results section lists inherited copy-number variants in several genes, but not DOCK4. A search of our copy for DOCK4 and for DOCK4 deletions, duplications, and single-nucleotide variants found no passage addressing DOCK4 variation in ASD (page numbers unavailable). (LLM, conf=0.75)
- Partly supportedcites [23] Warrier V, Chakrabarti B, Murphy L, Chan A, Craig I, Mallya U, et al. A pooled genome-wide association study of asperger syndrome. PloS ONE. 2015;10:e0131202. sourceExperimental — accuracy not yet measured
The Discussion identifies an intronic DOCK4 SNP as nominally associated in the Asperger syndrome study, and the References list earlier work on DOCK4 deletions and copy-number variation in the IMMP2L–DOCK4 region. But the paper does not identify DOCK4 duplications specifically. It also reports that its SNP did not remain significant after correction or show a significant association in a larger autism-spectrum cohort. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [24] Shao S, Kong R, Zou L, Zhong R, Lou J, Zhou J, et al. The roles of genes in the neuronal migration and neurite outgrowth network in developmental dyslexia: single- and multiple-risk genetic variants. Mol Neurobiol. 2016;53:3967–75. source
- Could not verifycites [25] Lim ET, Uddin M, De Rubeis S, Chan Y, Kamumbu AS, Zhang X, et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci. 2017;20:1217–24. sourceExperimental — accuracy not yet measured
The Introduction discusses copy-number variants and point mutations associated with ASD generally, but does not identify DOCK4. Searches of our copy for DOCK4 and DOCK4-associated SNVs, microdeletions, and duplications returned no passage addressing the gene-specific claim. No page numbers were supplied for these passages. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [26] Kushima I, Aleksic B, Nakatochi M, Shimamura T, Okada T, Uno Y, et al. Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights. Cell Rep. 2018;24:2838–56. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“This altered vocal behavior was reminiscent of some ASD mice models 33–35, suggesting abnormal communication in Dock4 KO mice.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
What the sources say
- Supportedcites [33] Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, et al. Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell. 2009;137:1235–46. source
In Results (‘patDp/+ Mice Display Social Abnormalities’), the source reports altered vocalizations in its autism-related mouse model and concludes that vocal communication is decreased. The citation supports the comparison to another mouse model with altered vocal behavior; the inference about Dock4 KO mice is the citing authors’ own. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [34] Schmeisser MJ, Ey E, Wegener S, Bockmann J, Stempel AV, Kuebler A, et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature. 2012;486:256–60. source
- Supportedcites [35] Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature. 2012;488:647–51. source
The main text reports increased ultrasonic vocalizations in Purkinje cell Tsc1 heterozygous and mutant pups, describing them as similar to reported ASD mouse models. This supports the citation’s role as an example of altered vocal behavior in an ASD mouse model; the inference about Dock4 KO mice is the citing authors’ own. (LLM, conf=0.91)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Ultrasonic vocalizations in pups when isolated from their dam measure language communication in mice.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“First, Rac1 appears to activate mTOR and its downstream target p70S6K (70-kDa ribosomal S6 kinase) 57, 58, a kinase essential for switching on translation initiation 48, 49.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Not checked — no full text of the sourcecites [57] Chou MM, Blenis J. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Cell. 1996;85:573–83. source
- Supportedcites [58] Saci A, Cantley LC, Carpenter CL. Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size. Mol Cell. 2011;42:50–61. source
The Discussion states that Rac1 regulates mTORC1 and mTORC2 activity. In the Results, deleting Rac1 reduced phosphorylation of S6K, an mTORC1 target, and restoring Rac1 rescued it. The claim does not require Rac1 itself to be in its GTP-bound active state. (LLM, conf=0.91)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, active Rac1 recruits CYFIP (cytoplasmic FMRP1-interacting protein) from the CYFIP-FMRP1 complex 59, and this Rac1-dependent shuttling of CYFIP interferes with the translation-inhibition function of FMRP1 and thereby leads to translational activation.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Supportedcites [59] De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A, et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron. 2013;79:1169–82. source
The Results sections on synaptic stimulation and Rac1-regulated translation report that active Rac1 shifts CYFIP1 away from the eIF4E-associated inhibitory complex, reducing FMRP’s association with eIF4E. The paper says this lifts translation inhibition and shows Rac1-dependent synthesis of the FMRP target ARC. It describes the switch more precisely as movement from the CYFIP1–eIF4E complex toward the WRC. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Variations in the gene encoding GluN2B have been frequently identified in neuropsychiatric disorders 62, 63, and studies on animal models have shown that GluN2B is particularly critical for social behaviors 61, 64, 65.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Not checked — no full text of the sourcecites [61] Lee EJ, Choi SY, Kim E. NMDA receptor dysfunction in autism spectrum disorders. Curr Opin Pharmacol. 2015;20:8–13. source
- Supportedcites [64] Wang CC, Held RG, Chang SC, Yang L, Delpire E, Ghosh A, et al. A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron. 2011;72:789–805. source
The Discussion states that GluN2B is a critical regulator of social behavior. The paper also reports reduced social exploration in mice after developmental loss of GluN2B (Highlights; page numbers not provided). (LLM, conf=0.93)
- Partly supportedcites [65] Jacobs S, Wei W, Wang D, Tsien JZ. Importance of the GluN2B carboxy-terminal domain for enhancement of social memories. Learn Mem. 2015;22:401–10. sourceExperimental — accuracy not yet measured
The Conclusions (page not provided) report that the GluN2B carboxy-terminal domain is essential for enhanced social recognition memory in transgenic mice. This supports a role in a specific social-memory task, but not the broader claim that GluN2B is particularly critical for social behaviors generally. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, active Rac1 recruits CYFIP (cytoplasmic FMRP1-interacting protein) from the CYFIP-FMRP1 complex 59, and this Rac1-dependent shuttling of CYFIP interferes with the translation-inhibition function of FMRP1 and thereby leads to translational activation.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Supportedcites [59] De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A, et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron. 2013;79:1169–82. source
The Results section reports that active Rac1 reduces CYFIP1 and FMRP association with eIF4E, while Rac1 inhibition prevents CYFIP1 redistribution. The paper also describes active Rac1 promoting CYFIP1 recruitment to the WRC, supporting the cited account of CYFIP1 moving away from the translation-inhibitory complex. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- It may state two separate claims as one. 14
- Probably not a substantial claim. 16
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Rac1, a master actin regulator, plays critical roles in modulating both the localization of neurotransmitter receptors and the architecture of excitatory synapses 3.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Partly supportedcites [3] Tejada-Simon MV. Modulation of actin dynamics by Rac1 to target cognitive function. J Neurochem. 2015;133:767–79. sourceExperimental — accuracy not yet measured
The Abstract describes Rac1 as an actin regulator important for dendritic spine morphogenesis, supporting its role in excitatory-synapse architecture. The section “Actin dynamics in neurons: link to intellectual disability” says glutamate receptors regulate Rac1, but does not say Rac1 controls the localization of neurotransmitter receptors; it describes Rac1 itself moving to the membrane after NMDA receptor activation. No page number is supplied for these passages. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Rac1 activity is tightly controlled by Rac1 guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), two protein families that directly activate and inhibit Rac1, respectively 16.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Supportedcites [16] Bai Y, Xiang X, Liang C, Shi L. Regulating Rac in the nervous system: molecular function and disease implication of Rac GEFs and GAPs. BioMed Res Int. 2015;2015:632450. source
The Introduction identifies Rac1 as a Rho GTPase and says GEFs and GAPs tightly control Rho GTPase activity. It explains that GEFs activate these proteins by promoting GDP–GTP exchange, while GAPs suppress them by accelerating GTP hydrolysis. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, both excessive and insufficient Rac1 activity induced by missense mutations in RAC1 itself cause developmental disorders presenting diverse phenotypes 11.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Supportedcites [11] Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, et al. RAC1 missense mutations in developmental disorders with diverse phenotypes. Am J Hum Genet. 2017;101:466–77. source
The paper’s Abstract reports developmental disorders with diverse phenotypes in seven people with de novo missense RAC1 mutations. It identifies two variants as dominant-negative and another as constitutively active, supporting the claim that both reduced and excessive RAC1 activity are associated with these disorders. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Besides the core symptoms, ASD subjects commonly present co-occurring symptoms that include anxiety and intellectual disability 37, 38.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Elevated anxiety and defective learning and memory in Dock4 KO mice
What the sources say
- Partly supportedcites [37] Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008;47:921–9. sourceExperimental — accuracy not yet measured
The Abstract and Rates of Disorder section report that anxiety disorders are common among the children with ASD studied, including social anxiety disorder in 29.2%. The Measures section reports a wide IQ range but does not establish that intellectual disability is a common co-occurring condition in this sample; it also does not classify intellectual disability as a symptom. Page numbers are not available in our copy. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [38] Eussen ML, Van Gool AR, Verheij F, De Nijs PF, Verhulst FC, Greaves-Lord K. The association of quality of social relations, symptom severity and intelligence with anxiety in children with autism spectrum disorders. Autism. 2013;17:723–35. source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Dock4 has been found to plays critical roles in axon guidance, dendritic development, and dendritic spine formation, but these results were obtained from in vitro preparations 27, 29–31.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Not checked — no full text of the sourcecites [27] Xiao Y, Peng Y, Wan J, Tang G, Chen Y, Tang J, et al. The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. J Biol Chem. 2013;288:20034–45. source
- Not checked — no full text of the sourcecites [29] Ueda S, Fujimoto S, Hiramoto K, Negishi M, Katoh H. Dock4 regulates dendritic development in hippocampal neurons. J Neurosci Res. 2008;86:3052–61. source
- Partly supportedcites [30] Ueda S, Negishi M, Katoh H. Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation. Mol Biol Cell. 2013;24:1602–13. sourceExperimental — accuracy not yet measured
The Results section (‘Knockdown of Dock4 reduces dendritic spine density’; page unavailable) reports that Dock4 knockdown impaired spine formation in cultured rat hippocampal neurons, supporting the in vitro spine-formation part of the claim. The passages found do not establish roles for Dock4 in axon guidance or broader dendritic development. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [31] Makihara S, Morin S, Ferent J, Cote JF, Yam PT, Charron F. Polarized dock activity drives shh-mediated axon guidance. Dev Cell. 2018;46:410–25 e417. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“DOCK4 is located at chromosome band 7q31.1 18, 19, an autism-susceptible locus resided by several ASD-associated genes involved in development and language regulation.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Partly supportedcites [18] Maestrini E, Pagnamenta AT, Lamb JA, Bacchelli E, Sykes NH, Sousa I, et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry. 2010;15:954–68. sourceExperimental — accuracy not yet measured
The Discussion identifies the IMMP2L/DOCK4 locus on chromosome 7 as a possible contributor to autism susceptibility, and the Introduction places the studied locus on chromosome 7q. Our copy does not specify that DOCK4 is at the narrower band 7q31.1, so that precise location is not verified. (LLM, conf=0.83)
- Supportedcites [19] Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, Minopoli F, et al. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry. 2010;68:320–8. source
The Abstract Methods place the DOCK4 microdeletion at 7q31.1. The passage labeled Abstract Conclusions identifies the chromosome 7q region as autism susceptibility locus 1 (AUTS1) and reports evidence implicating DOCK4 in autism susceptibility. Page numbers are not supplied in our copy. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Variations in the gene encoding GluN2B have been frequently identified in neuropsychiatric disorders 62, 63, and studies on animal models have shown that GluN2B is particularly critical for social behaviors 61, 64, 65.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Supportedcites [62] Liu S, Zhou L, Yuan H, Vieira M, Sanz-Clemente A, Badger JD 2nd, et al. A rare variant identified within the GluN2B C-terminus in a patient with autism affects NMDA receptor surface expression and spine density. J Neurosci. 2017;37:4093–102. source
The Introduction reports multiple studies identifying GluN2B missense variants in patients with schizophrenia, autism, and other neurological or psychiatric diseases. This supports the cited clause about variants being frequently identified; the separate animal-model clause has different citations. (LLM, conf=0.90)
- Supportedcites [63] Fedele L, Newcombe J, Topf M, Gibb A, Harvey RJ, Smart TG. Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun. 2018;9:957. source
The Introduction identifies multiple GluN2B mutations associated with neurodevelopmental disorders, including autism-related features and intellectual disability. The Results report examining 13 GluN2B mutations associated with such disorders, supporting the broad statement that variants have been identified repeatedly. The paper does not quantify how often they occur in patients. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Bidirectional changes of E/I ratio of synaptic inputs in different brain regions have been implicated in ASD pathology 60.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Supportedcites [60] Gatto CL, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci. 2010;2:4. source
The Autism section reports increased inhibitory synaptic input in the somatosensory barrel cortex of an ASD mouse model, while hippocampal culture studies of an ASD-related variant showed reduced inhibitory activity. It concludes that E/I imbalance can present differently in various circuits. The evidence is from ASD models, rather than a direct comparison of brain regions in people with ASD. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“First, Rac1 appears to activate mTOR and its downstream target p70S6K (70-kDa ribosomal S6 kinase) 57, 58, a kinase essential for switching on translation initiation 48, 49.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
What the sources say
- Partly supportedcites [48] Bhattacharya A, Mamcarz M, Mullins C, Choudhury A, Boyle RG, Smith DG, et al. Targeting translation control with p70 S6 Kinase 1 inhibitors to reverse phenotypes in fragile X syndrome mice. Neuropsychopharmacology. 2016;41:1991–2000. sourceExperimental — accuracy not yet measured
The Introduction says S6K1 promotes cap-dependent translation initiation by stimulating eIF4A activity, supporting its role in initiation. It does not say S6K1 is essential for switching initiation on; that necessity is stronger than the passage supports. No page number is provided in our copy. (LLM, conf=0.86)
- Could not verifycites [49] Berg JM, Lee C, Chen L, Galvan L, Cepeda C, Chen JY, et al. JAKMIP1, a novel regulator of neuronal translation, modulates synaptic function and autistic-like behaviors in mouse. Neuron. 2015;88:1173–91. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says that PABPC1 is required for translation initiation, but it does not make that statement about p70S6K. Searches for p70S6K, S6K, and the claimed kinase role found no passage in our copy addressing whether p70S6K is essential for switching on translation initiation. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No Dock4 was detected in any brain region or other organs in KO mice, whereas reduced amounts of Dock4 were found in the corresponding HET tissues (Figure 1c, Supplementary Figure 3f).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite showing slightly lower natality (Supplementary Figure 4a), Dock4 HET and KO mice exhibited similar growth rate (weight gain; Supplementary Figure 4b,c), ingestion, and mating as WT mice did.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Dock4 transcript was completely absent in the KO brain and reduced by approximately half in the HET brain (Figure 1b, Supplementary Figure 3d).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In accord with previous observations 27, Dock4 was found to be expressed in various brain regions and highly enriched in the hippocampus (Figure 1c).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
What the sources say
- Not checked — no full text of the sourcecites [27] Xiao Y, Peng Y, Wan J, Tang G, Chen Y, Tang J, et al. The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics. J Biol Chem. 2013;288:20034–45. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The male HET and KO mice and the majority of the female HET and KO mice displayed mostly normal locomotion in the open field (Figure 1f) and did not show stereotyped behaviors (Supplementary Figure 5b,c).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and the brain was slightly heavier in female KO mice than in female WT mice (Figure 1e).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the social approach phase, WT, HET, and KO mice all performed normally, spending more time exploring the stranger conspecific than the object (Figure 1i–k; Supplementary Figure 6f,g).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A Dock4 KO mouse line was established, and the loss of Dock4 expression in the mice was verified using quantitative real-time PCR (qRT-PCR) and western blotting (Figure 1a, Supplementary Figures 2 and 3).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Brain architecture in Dock4 KO mice was grossly normal, with slight enlargement of the lateral ventricles (Figure 1d, Supplementary Figure 4d–g)”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Reduction of some AMPA and NMDA subunits was also observed in prefrontal cortex, but not striatum and cerebellum of KO mice (Supplementary Figure 11).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Disrupted AMPA and NMDA receptor functions in Dock4 KO hippocampus
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings further unravel that NMDAR hypofunction-induced failure of excitatory synaptic function is a main cause of social deficit in Dock4 KO mice, as NMDAR-mediated synaptic transmission and plasticity were impaired, and the NMDA agonist DCS restored normal social behavior.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“ASD exhibits a strong genetic basis, and increasing evidence from inherited and de novo gene variations suggests a notable convergence on synapse pathophysiology in ASD, particularly dysfunction of excitatory synaptic transmission 1, 2.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16:551–63. source
- Not checked — no full text of the sourcecites [2] Joensuu M, Lanoue V, Hotulainen P. Dendritic spine actin cytoskeleton in autism spectrum disorder. Prog neuro-Psychopharmacol Biol Psychiatry. 2018;84(Pt B):362–81. source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For virus injection and drug treatment studies, animals were randomly assigned to two groups, each according to gender (male: female ratio is roughly 1:1) and body weight.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Materials and Methods > Behavioral tests
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, characterizations of the ASD core symptoms revealed that Dock4 KO mice exhibited both language and social deficits, and displayed increased tendency of stereotyped behavior.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Dock4 KO mice exhibit social deficits
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Ultrasonic vocalizations in pups when isolated from their dam measure language communication in mice.
- Rests on an assumption: The pup-retrieval assay measures maternal behavior in mice.
- Rests on an assumption: The hyperactivity, stereotyped behavior, and social/communication deficits observed in Dock4 mutant mice are autism-like or ASD core symptoms.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Neuro-2a cells were purchased from ATCC and were routinely tested for mycoplasma contamination-free before use.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Materials and Methods > Antibodies and reagents
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Investigators were blind to genotype or treatment of the mice being tested during all experiments.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Materials and Methods > Behavioral tests
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sample size chosen for each study was established by previous pilot and published studies.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Materials and Methods > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“normal distribution and similar variance within each comparison group of data were checked before any parametric analyses; P < 0.05 was considered significant.”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Materials and Methods > Statistics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Whereas both forms of LTD were hardly induced at adult as reported 40, they are similarly induced in WT and KO hippocampus at young postnatal age, suggesting that LTD is intact in KO mice (Supplementary Figure 9).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Disrupted AMPA and NMDA receptor functions in Dock4 KO hippocampus
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“Whereas both forms of LTD were hardly induced at adult as reported 40, they are similarly induced in WT and KO hippocampus at young postnatal age, suggesting that LTD is intact in KO mice (Supplementary Figure 9).”
§ Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function > Results > Disrupted AMPA and NMDA receptor functions in Dock4 KO hippocampus
What the sources say
- Not checked — no full text of the sourcecites [40] Khoo GH, Lin YT, Tsai TC, Hsu KS. Perineuronal nets restrict the induction of long-term depression in the mouse hippocampal CA1 region. Mol Neurobiol. 2019;56:6436–50. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The 61-aa truncated Dock4 protein produced by the null allele is nonfunctional.
“Because of the deletion and the resulting frameshift, the null allele generates a 61-aa truncated protein (41 aa of Dock4 N-terminal sequence and 20 aa of frame-shifted nonsense sequence) instead of the full-length 1978 aa protein (Supplementary Figure 2 and 3, Supplementary methods).”
The paper relies on this without support.
Social novelty preference deficit in mice is a valid model of ASD social deficits.
“We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning.”
The paper relies on this without support.
Many DOCK4 variations associated with ASD result in loss-of-function.
“Many of these variations are believed to result in loss-of-function of DOCK4.”
The paper relies on this without support.
Nesting ability in mice tightly correlates with social behaviors such as parenting and reproduction.
“First, the ability of nesting, a nature in mice that tightly correlates with social behaviors such as parenting and reproduction, was evaluated.”
The paper relies on this without support.
Ultrasonic vocalizations in pups when isolated from their dam measure language communication in mice.
“To investigate language communication in Dock4 KO mice, we evaluated ultrasonic vocalizations in pups when isolated from their dam within the first two weeks after birth.”
The paper relies on this without support.
The pup-retrieval assay measures maternal behavior in mice.
“Second, maternal behavior was measured in a pup-retrieval assay by using virgin female mice.”
The paper relies on this without support.
The hyperactivity, stereotyped behavior, and social/communication deficits observed in Dock4 mutant mice are autism-like or ASD core symptoms.
“Notably, a small population of female HET (1.7%) and KO (9.1%) mice showed autism-like hyperactivity and stereotyped behavior, such as continual circling in the home cage and open field (Figure 1f, Supplementary Figure 5a, Supplementary Videos 1–3).”
The paper relies on this without support.
NMDAR function is important for the induction of both long-term potentiation (LTP) and long-term depression (LTD).
“Because NMDAR function is important for the induction of both long-term potentiation (LTP) and long-term depression (LTD), we examined whether these two forms of synaptic plasticity are altered by Dock4 deficiency.”
The paper relies on this without support.
Rac1 is a well-studied actin regulator required for normal synaptic function that acts through diverse downstream effectors.
“Rac1 is a well-studied actin regulator required for normal synaptic function that acts through diverse downstream effectors.”
The paper relies on this without support.
Rac1 is a converging factor that receives signals from different ASD genes.
“Thus, Rac1, as a converging factor that receiving signals from different ASD genes, might exert dual effects on actin dynamics as well as protein synthesis depending on the context of synaptic regulation.”
The paper relies on this without support.
Normalization of Rac1 activity corrects ASD-like behaviors in a variety of animal models.
“The fact that normalization of Rac1 activity corrects ASD-like behaviors in a variety of animal models suggests that targeting Rac1 may be a potential therapeutic approach for ASD.”
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?
The cited source says what the claim attributes to it.
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“In particular, impairment of Dock4-dependent excitatory synapse transmission in hippocampal CA1 pyramidal neurons is a main cause for the social deficits (Guo et al., 2019).”
From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Guo et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Our previous study using Dock4 knockout mice have revealed that Dock4 deficiency in vivo leads to autism-like behaviors, including defects in social novelty preference and communication (Guo et al., 2019).”
From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Guo et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Previous studies in both Dock4 KO mice and in Dock4-shRNA knockdown neurons have shown that Dock4 promotes dendritic spine formation and excitatory synaptic transmission in hippocampus (Ueda et al., 2013; Guo et al., 2019).”
From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Guo et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Using Dock4 knockout mice, we have shown that deficiency of Dock4 in vivo leads to social and communication deficits (Guo et al., 2019).”
From Two Autism/Dyslexia Linked Variations of DOCK4 Disrupt the Gene Function on Rac1/Rap1 Activation, Neurite Outgrowth, and Synapse Development (2020) · cites this paper as Guo et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“loss of DOCK4 function is compensated by overexpression of the DOCK4 interacting partner RAC1, as demonstrated in vitro (Huang et al. 2019) and in vivo (Guo et al. 2021)”
From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Guo et al. 2021
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“Heterozygous (Dock4 HET) mice also show defective social novelty preference and disrupted spatial memory in Y-maze [70] (Table 2; Supplementary Table S1).”
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“It is thus possible that increased GSK3 activity would inhibits CREB (leading to impaired Frontiers in Molecular Neuroscience 07 frontiersin.org LTP and strengthened LTD), whereas inactivation of GSK3 would restore CREB activity and induces LTP. Paradoxically, studies of chronic lithium treatment impact on CREB found…”
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“…bherring@usc.edu. https://doi.org/10.1523/JNEUROSCI.3148-20.2021 Copyright © 2021 the authors proposed as a promising candidate of convergence of many ASD risk factors (Schenck et al., 2003; Dolan et al., 2013; ZeidánChuliá et al., 2013; Duffney et al., 2015; Tian et al., 2018; Guo et al., 2021).”
BackgroundInfluential
Metadata
- Authors
- Guo, D., Peng, Y., Wang, L., Sun, X., Wang, X., Liang, C., Yang, X., Li, S., Xu, J., Ye, W.-C., Jiang, B., & Shi, L.
- Affiliations
- Jinan University (CN)
- Sun Yat-sen University (CN)
- Zhejiang University (CN)
- Corresponding author
- Ye, Wen-Cai
- Jiang, Bin
- Shi, Lei
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2019-08-06
- Volume
- 26
- Issue
- 5
- Pages
- 1505-1519
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC8159750
- OpenAlex
- W2965158022
- Semantic Scholar
- cedd6bfac86f82c00198fcb53150038fd72db66c
- Cited by
- 102
- References
- 66
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 25 · 2023: 13 · 2022: 20 · 2021: 15 · 2020: 7
- FWCI
- 5.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Academy of Medical Sciences (AOMS-NAF0051003)
- National Natural Science Foundation of China (81761130084, 81870869)
- China Postdoctoral Science Foundation
- Guangdong Science and Technology Department (2017BT01Y036)
- The National Key R&D Program of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, DOCK4, Rac1, NMDA receptor, AMPA receptors, excitatory synaptic transmission, social behavior, social novelty preference, hippocampal CA1, synaptic dysfunction, protein synthesis, glutamate receptors, anxiety, spatial learning
- MeSH terms
- Autism Spectrum Disorder, Animals, Autistic Disorder, Hippocampus, Synaptic Transmission, Neuropeptides, Receptors, N-Methyl-D-Aspartate, Mice, Knockout, GTPase-Activating Proteins, rac1 GTP-Binding Protein, Mice
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