Disparate Effects of Lithium and a GSK-3 Inhibitor on Neuronal Oscillatory Activity in Prefrontal Cortex and Hippocampus

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.

Lithium enhances exercise-induced glycogen breakdown and insulin-induced AKT activation to facilitate glucose uptake in rodent skeletal muscle

“…3b ). Reportedly, AKT and GSK3β are linked to Li effects on glucose uptake [ 29 ]; therefore, we determined the effects of Li with low-intensity (12 m/min, Li/Low-Ex) for 20 min and moderate-intensity (20 m/min, Li/Mo-Ex) exercise for 40 min on AKT and GSK3β protein content. We found that Li with Mo-Ex significantly decreased muscle glycogen levels (Fig.…”

The GSK-3 Inhibitor CT99021 Enhances the Acquisition of Spatial Learning and the Accuracy of Spatial Memory

“…The use of genetically modified mice has implicated GSK-3 in a variety of higher cognitive functions, such as spatial learning and memory (Hernandez et al, 2002;Liu et al, 2003), novel object recognition memory (Engel et al, 2006;Pardo et al, 2015) and social behaviors (Khlghatyan and Beaulieu, 2020). In terms of pharmacology, GSK-3 inhibitors lead to enhanced memory in the passive avoidance task (Yuskaitis et al, 2010), cued fear conditioning (Watase et al, 2007;Lipina et al, 2013), spatial learning (Nguyen et al, 2017) and object recognition memory (Lipina et al, 2013). The mechanism that likely underlies GSK-3's role in these cognitive processes is altered synaptic plasticity (Bradley et al, 2012).…”

GSK-3β disrupts neural oscillatory function to inhibit learning and memory in rats

“…The consistent demonstration of increased GSK-3β activity in disorders of cognitive decline, coincident with alterations in neural oscillatory function, suggests a potential coupling of the two mechanisms. Indeed, this idea is supported by our previous evidence showing that the systemic and short-term pharmacological inhibition of GSK-3 in rats altered neural oscillatory patterns within the PFC and HIP, that were associated with improved learning and memory [44]. This study sought to expand on those findings to evaluate a direct role for GSK-3β within the PFC or HIP in the regulation of neural oscillatory activity and learning and memory processes.…”