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- W2183631902 abstract "Shank3,whichencodesascaffoldingproteinatglutamatergicsynapses,isageneticriskfactorforautism.Inthisstudy,weexaminedthe 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 dynamicsisregulatedbytheGTPaseRac1anddownstreameffectorp21-activatedkinase(PAK),wefurtherexaminedShank3regulation ofNMDARswhenRac1orPAKwasmanipulated.WefoundthatthereducingeffectofShank3siRNAonNMDARcurrentswasmimicked 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 primarydownstreamtargetofPAKandamajoractindepolymerizingfactor,preventedShank3siRNAfromreducingNMDARcurrents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actinsignaling,leadingtothelossofNMDARmembranedeliveryorstability.Itprovidesapotentialmechanismforthe roleofShank3incognitivedeficitinautism." @default.
- W2183631902 created "2016-06-24" @default.
- W2183631902 creator A5067224472 @default.
- W2183631902 date "2013-01-01" @default.
- W2183631902 modified "2023-09-27" @default.
- W2183631902 title "Shank3DeficiencyInducesNMDAReceptorHypofunction viaanActin-DependentMechanism" @default.
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