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GSK3? 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-3? (GSK3?) plays a critical role in synaptic plasticity during development and is highly implicated in the etiology of SZ. However, how GSK3? activity affects synaptic plasticity and working memory function in the prefrontal cortex (PFC) during development remains unknown. Here we show a GSK3? 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 GSK3? inhibitor during the juvenile period. Furthermore, the age-dependent hyperactive GSK3? 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 GSK3? 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 GSK3? likely accounts for the cortical spine loss and PFC-dependent cognitive deficits in adulthood. These results highlight the importance of the postnatal trajectory of GSK3? for spine development and PFC function, and may shed light on the prophylactic treatment of cognitive symptoms in the SZ.

SUBMITTER: Xing B

PROVIDER: S-EPMC5101547 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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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.

Xing Bo B Li Yan-Chun YC Gao Wen-Jun WJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160629 13

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 ...[more]

PMID: 27353310

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Project description:The ventromedial prefrontal cortex (vmPFC) regulates fear acquisition, fear extinction, mood, and HPA axis function. Multiple brain regions exhibit time-of-day dependent variations in learning, long term potentiation (LTP), and dendritic morphology. Glucocorticoids have been implicated in the regulation of dendritic structure in the context of stress. Glucocorticoids are also known to regulate molecular clock entrainment via upregulation of Per1 transcription. In the present study, C57BL/6 N mice were sacrificed at three distinct times of day (ZT3, ZT12, and ZT16, lights off at ZT12) and Per1 mRNA expression was measured in the infralimbic and prelimbic vmPFC subregions using droplet digital (dd) PCR after recovering from adrenalectomy or sham surgery for 10 days. Sham mice showed Per1 rhythmicity in both infralimbic (IL) and prelimbic (PL) cortex, with peak expression occurring at ZT12. Adrenalectomized mice showed reductions in Per1 amplitude at ZT12 in both IL and PL, suggesting that the vmPFC molecular clock is entrained by diurnal glucocorticoid oscillations. Thy1-eGFP mice were used to visualize and quantify dendritic spine density on deep layer pyramidal dendrites at ZT 3, 12, and 16. Spine density in both PL and IL exhibited changes between the light (inactive) and dark (active) phases, with peak spine density observed at ZT16 and trough spine density observed at ZT3. These changes in spine density were restricted to changes in long thin and stubby type spines. To determine if changes in spine density is regulated by glucocorticoid oscillations, the 11β-hydroxylase inhibitor metyrapone was administered 2 h prior to the onset of the active phase (ZT10) daily for 7 days. Metyrapone administration blocked both the diurnal peak of plasma corticosterone and peak spine densities in the IL and PL at ZT16. These results suggest that vmPFC molecular clock gene and dendritic spine diurnal rhythms depend on intact diurnal glucocorticoid oscillations.

Dataset Information

GSK3? Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory.

Publications

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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