The DOI matches its Crossref record; 86 of the 87 references it cites were found in a registry or an index.
Shank3 Deficiency Induces NMDA Receptor Hypofunction via an Actin-Dependent Mechanism
Open accessAbstract
Shank3, which encodes a scaffolding protein at glutamatergic synapses, is a genetic risk factor for autism. In this study, we examined the impact of Shank3 deficiency on the NMDA-type glutamate receptor, a key player in cognition and mental illnesses. We found that knockdown of Shank3 with a small interfering RNA (siRNA) caused a significant reduction of NMDAR-mediated ionic or synaptic current, as well as the surface expression of NR1 subunits, in rat cortical cultures. The effect of Shank3 siRNA on NMDAR currents was blocked by an actin stabilizer, and was occluded by an actin destabilizer, suggesting the involvement of actin cytoskeleton. Since actin dynamics is regulated by the GTPase Rac1 and downstream effector p21-activated kinase (PAK), we further examined Shank3 regulation of NMDARs when Rac1 or PAK was manipulated. We found that the reducing effect of Shank3 siRNA on NMDAR currents was mimicked and occluded by specific inhibitors for Rac1 or PAK, and was blocked by constitutively active Rac1 or PAK. Immunocytochemical data showed a strong reduction of F-actin clusters after Shank3 knockdown, which was occluded by a PAK inhibitor. Inhibiting cofilin, the primary downstream target of PAK and a major actin depolymerizing factor, prevented Shank3 siRNA from reducing NMDAR currents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actin signaling, leading to the loss of NMDAR membrane delivery or stability. It provides a potential mechanism for the role of Shank3 in cognitive deficit in autism.
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“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.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [4]
In the citing paper
“In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [24]
In the citing paper
“These mutations are also often related to excitatory synaptic dysfunction and neurotransmission that may be potentially restorable 24,29,30.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [24]
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Cites
Krystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330
Recent advances in the phencyclidine model of schizophrenia
(1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.10.1301 · Cited by 2,904
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795
In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse
Schwarze, S. R., Ho, A. L., Vocero-Akbani, A. M., & Dowdy, S. F. (1999) · Science · doi:10.1126/science.285.5433.1569 · Cited by 2,418
McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A. S., Zackai, E. H., Emanuel, B. S., Vermeesch, J. R., Morrow, B. E., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.71 · Cited by 2,236
Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsäter, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1933 · Cited by 1,602
Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G. (2011) · Nature · doi:10.1038/nature09965 · Cited by 1,570
A brain serine/threonine protein kinase activated by Cdc42 and Rac1
Manser, E. J., Leung, T., Salihuddin, H., Zhao, Z.-S., & Lim, L. (1994) · Nature · doi:10.1038/367040a0 · Cited by 1,541
Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking
Ridley, A. J. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.08.006 · Cited by 1,215
Biology of the p21-Activated Kinases
Bokoch, G. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161742 · Cited by 1,080
Research works printed but not linked: 1
- 10.1002/1098-1063(2000)10:5<542::AID-HIPO4>3.0.CO;2-7 · DOI
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Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516
Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators
Duffney, L. J., Zhong, P., Wei, J., Matas, E., Cheng, J., Qin, L., Ma, K., Dietz, D. M., Kajiwara, Y., Buxbaum, J. D., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.064 · Cited by 281
“Previous studies have shown that NMDAR membrane delivery and stability is dependent on the integrity of actin cytoskeleton (Rosenmund and Westbrook, 1993; Allison et al., 1998; Morishita et al., 2005; Duffney et al., 2013).”
Self-citationQin, L., Ma, K., Wang, Z.-J., Hu, Z., Matas, E., Wei, J., & Yan, Z. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0110-8 · Cited by 240
Self-citationRojas, D. C. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1216-0 · Cited by 195
“Although the size of the deleted region varies, the SHANK3 gene is nearly always included.”
BackgroundInfluentialOxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat
Harony-Nicolas, H., Kay, M., Hoffmann, J. D., Klein, M. E., Bozdagi-Gunal, O., Riad, M., Daskalakis, N. P., Sonar, S., Castillo, P. E., Hof, P. R., et al. (2017) · eLife · doi:10.7554/elife.18904 · Cited by 168
“…in the levels of glutamatergic receptors and other PSD scaffolding components including Homer, which we also found to be decreased in the Shank3-deficient rat (Figure 1—figure supplement 1C) (Bozdagi et al., 2010; Wang et al., 2011; Duffney et al., 2013; Kouser et al., 2013; Wang et al., 2016).”
Background
Metadata
- Authors
- Duffney, L. J., Wei, J., Cheng, J., Liu, W., Smith, K. R., Kittler, J. T., & Yan, Z.
- Affiliations
- University College London (GB)
- University at Buffalo, State University of New York (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-10-02
- Volume
- 33
- Issue
- 40
- Pages
- 15767-15778
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3787498
- OpenAlex
- W2045491381
- Cited by
- 115
- References
- 87
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 12 · 2021: 14 · 2020: 12 · 2019: 5 · 2018: 11 · 2017: 5 · 2016: 15 · 2015: 13 · 2014: 6
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (5r21mh101690-02, MH-101690)
- National Institute of Mental Health (R21-MH101690, R01MH085774)
- 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 › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- SHANK3, NMDA receptor hypofunction, actin cytoskeleton, Rac1, p21-activated kinase, cofilin, glutamatergic synapses, autism spectrum disorder, synaptic currents, cortical neurons, actin depolymerization
- MeSH terms
- Actins, Animals, Cells, Cultured, Cerebral Cortex, Humans, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Synapses, Receptors, N-Methyl-D-Aspartate, rac1 GTP-Binding Protein, RNA Interference, RNA, Small Interfering, Rats, p21-Activated Kinases, HEK293 Cells
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