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Decrease of GSK-3β Activity in the Anterior Cingulate Cortex of Shank3b -/- Mice Contributes to Synaptic and Social
Mengmeng Wang1, Xinyan Liu1, Yilin Hou1,2
1Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Frontiers in Cellular Neuroscience
|November 22, 2019
Summary
Shank3b mutation in mice impairs social behavior and synaptic development in the anterior cingulate cortex (ACC). Restoring glycogen synthase kinase 3β (GSK-3β) activity in the ACC improved social activity and synaptic function, suggesting a potential therapeutic target for autism spectrum disorders (ASD).
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Social deficiency is a core symptom of autism spectrum disorders (ASD), with underlying mechanisms still unclear.
- The anterior cingulate cortex (ACC) is crucial for social information processing and behavior regulation.
- Synaptic dysfunction in the ACC is implicated in ASD-related social deficits.
Purpose of the Study:
- To investigate synaptic development and the role of glycogen synthase kinase 3β (GSK-3β) in the ACC of Shank3b knockout mice, a model for ASD.
- To explore the potential of modulating GSK-3β activity as a therapeutic strategy for ASD social deficits.
Main Methods:
- Utilized Shank3b knockout mice (Shank3b-/-) as a model organism.
- Analyzed synaptic structure, spine density, post-synaptic density (PSD) components (PSD95, GluR2, vGlut2), and miniature excitatory post-synaptic currents (mEPSCs) in the ACC.
- Investigated the activity of GSK-3β and its phosphorylated form (pGSK-3β Ser9).
- Administered adeno-associated virus (AAV) expressing active GSK-3β to the ACC.
- Assessed social behavior in Shank3b-/- mice following GSK-3β modulation.
Main Results:
- Shank3b mutation abolished social-induced c-Fos expression and led to decreased spine density and altered spine morphology in the ACC.
- Synaptic deficits, including reduced PSD length/thickness, vGlut2 and GluR2 expression, and mEPSC frequency, were observed in Shank3b-/- ACC.
- Shank3b mutation increased inhibitory phosphorylation of GSK-3β (pGSK-3β Ser9) and decreased GluR2 and pPSD95 levels.
- Restoring GSK-3β activity via AAV delivery normalized GluR2 expression, increased spine density, and significantly improved social activity in Shank3b-/- mice.
Conclusions:
- Reduced GSK-3β activity in the ACC contributes to synaptic and social deficits in Shank3b-/- mice, a model of ASD.
- Modulating GSK-3β activity represents a promising therapeutic avenue for addressing synaptic and social impairments in ASD.
- Targeting GSK-3β in the ACC may offer a novel strategy for treating autism spectrum disorders.
