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GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory
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GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory

Bo Xing, Yan-Chun Li and Wen-Jun Gao
Neuropsychopharmacology (New York, N.Y.), v 41(13), pp 3003-3015
Dec 2016
DOI: https://doi.org/10.1038/npp.2016.110
PMID: 27353310
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1038/npp.2016.110View
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Abstract

Animals, Newborn Age Factors Neuronal Plasticity - drug effects Rats Memory, Short-Term - drug effects Neurons - cytology Memory, Short-Term - physiology Prefrontal Cortex - growth & development Prenatal Exposure Delayed Effects - physiopathology Glycogen Synthase Kinase 3 beta - metabolism Methylazoxymethanol Acetate - pharmacology Prefrontal Cortex - pathology Pregnancy Animals Neuronal Plasticity - physiology Long-Term Potentiation - drug effects Signal Transduction - drug effects Long-Term Potentiation - physiology Female Signal Transduction - physiology Protein Synthesis Inhibitors - pharmacology In Vitro Techniques
Schizophrenia (SZ) is a neurodevelopmental disorder in which the emergence of cognitive symptoms occurs during early adolescence. Glycogen synthase kinase-3β (GSK3β) plays a critical role in synaptic plasticity during development and is highly implicated in the etiology of SZ. However, how GSK3β activity affects synaptic plasticity and working memory function in the prefrontal cortex (PFC) during development remains unknown. Here we show a GSK3β hyperactivity during the early postnatal period in a neurodevelopmental rat SZ model that receives gestational exposure (E17) to the neurotoxin methylazoxymethanol (MAM). Accompanied with this change, adult MAM rats exhibited a significant decrease in spine density as well as impaired working memory, which was rescued by treatment with a GSK3β inhibitor during the juvenile period. Furthermore, the age-dependent hyperactive GSK3β caused a significant deficit in long-term potentiation (LTP) and facilitated long-term depression (LTD) in PFC pyramidal neurons. Notably, these changes in synaptic plasticity occurred only during the late juvenile period and were efficiently reversed by application of GSK3β inhibitors. Because the balance of LTP and LTD plays a critical role in activity-dependent synaptic stabilization and elimination during cortical development, the transient hyperactive GSK3β likely accounts for the cortical spine loss and PFC-dependent cognitive deficits in adulthood. These results highlight the importance of the postnatal trajectory of GSK3β for spine development and PFC function, and may shed light on the prophylactic treatment of cognitive symptoms in the SZ.

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Collaboration types
International collaboration
Web of Science research areas
Neurosciences
Pharmacology & Pharmacy
Psychiatry
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