Abstract
Glycogen synthase kinase-3 (GSK-3) plays a critical role in cognitive dysfunction associated with Alzheimer’s disease (AD), yet the mechanism by which GSK-3 alters cognitive processes in other disorders, such as schizophrenia, remains unknown. In the present study, we demonstrated a role for GSK-3 in the direct regulation of neuronal oscillations in hippocampus (HIP) and prelimbic cortex (PL). A comparison of the GSK-3 inhibitors SB 216763 and lithium demonstrated disparate effects of the drugs on spatial memory and neural oscillatory activity in HIP and PL. SB 216763 administration improved spatial memory whereas lithium treatment had no effect. Analysis of neuronal local field potentials in anesthetized animals revealed that whereas both repeated SB 216763 (2.5 mg/kg) and lithium (100 mg/kg) induced a theta frequency spike in HIP at approximately 10 Hz, only SB 216763 treatment induced an overall increase in theta power (4–12 Hz) compared to vehicle. Acute administration of either drug suppressed slow (32–59 Hz) and fast (61–100 Hz) gamma power. In PL, both drugs induced an increase in theta power. Repeated SB 216763 increased HIP–PL coherence across all frequencies except delta, whereas lithium selectively suppressed delta coherence. These findings demonstrate that GSK-3 plays a direct role in the regulation of theta oscillations in regions critically involved in cognition, and highlight a potential mechanism by which GSK-3 may contribute to cognitive decline in disorders of cognitive dysfunction.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a constitutively active protein kinase with an array of physiological functions including mediating intracellular signaling, as well as regulating neuronal plasticity, gene expression, and cell survival (Grimes and Jope, 2001)
A disorder associated with cognitive dysfunction, a role for elevated GSK-3 activity in the neuropathology of this disorder is provided by postmortem findings, as well as genetic and behavioral studies
To assess cognitive flexibility, which requires prefrontal cortex (PFC) function (Graybeal et al, 2011), we evaluated the animals during a reversal learning task by shifting the platform to the opposite quadrant and evaluating the number of trials it took to learn the new location of the platform and escape
Summary
Glycogen synthase kinase-3 (GSK-3) is a constitutively active protein kinase with an array of physiological functions including mediating intracellular signaling, as well as regulating neuronal plasticity, gene expression, and cell survival (Grimes and Jope, 2001). Developmental inhibition of GSK-3 was shown to alleviate spatial memory deficiencies in a mouse model of schizophrenia predisposition (Tamura et al, 2016) indicative of a direct link between GSK-3 and the development of processes critical to aberrant cognitive functioning in this disorder In line with these findings GSK-3 has been shown to be involved in mediating reductions in cognitive performance associated with diabetes mellitus (King et al, 2013; Wang and Zhao, 2016), Fragile-X syndrome (Guo et al, 2012; Franklin et al, 2014; Pardo et al, 2017), and human immunodeficiency virus (Ances et al, 2008), and in a model of traumatic brain injury improvements in spatial memory induced by valproate were associated with inhibition of GSK-3 in hippocampus (Dash et al, 2010)
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