title: GSK3β Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory.
abstract: 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.
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.|Xi'an Mental Health Center, Xi'an, Shaanxi, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Wen-Jun
authors.identifier: 0000-0002-8585-3082
authors.initials: WJ
authors.lastname: Gao
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D008746:Methylazoxymethanol Acetate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D017397:Prefrontal Cortex / Q000254:growth & development / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D011500:Protein Synthesis Inhibitors; D008746:Methylazoxymethanol Acetate; D000071679:Glycogen Synthase Kinase 3 beta