GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity.

Area of Science:

• Neuroscience
• Chronobiology
• Molecular Biology

Background:

• Hippocampal rhythms in gene expression, enzyme activity, and long-term potentiation (LTP) influence daily memory variations.
• Glycogen synthase kinase 3-beta (GSK3β) regulates hippocampal function, with its inhibitory phosphorylation showing daily fluctuations.

Purpose of the Study:

• To investigate circadian rhythms in GSK3α and GSK3β phosphorylation within the hippocampus.
• To determine if chronic GSK3 inhibition or activation affects the molecular clock and hippocampal LTP.

Main Methods:

• Assessed circadian rhythms of GSK3α and GSK3β phosphorylation in mouse hippocampal CA1 under constant darkness.
• Utilized transgenic mice (GSK3-KI) for chronic GSK3 activation and pharmacological inhibitors for chronic GSK3 inhibition.
• Measured BMAL1 expression, molecular clock periodicity (PER2::LUC), and LTP magnitude in organotypic hippocampal cultures and mouse models.

Main Results:

• A significant circadian rhythm was found in GSK3β phosphorylation, but not GSK3α, in hippocampal CA1.
• Chronic GSK3 activation reduced BMAL1 rhythmicity, while GSK3 inhibition shortened the molecular clock period.
• Day-night differences in LTP were maintained with chronic GSK3 activation but impaired by GSK3 inhibition, particularly at night.

Conclusions:

• Circadian rhythmicity of hippocampal GSK3β activation state is crucial for regulating daily variations in molecular clock periodicity.
• GSK3β rhythmicity plays a key role in modulating day-night differences in hippocampal synaptic plasticity, specifically LTP.
• These findings support a model where GSK3β activity rhythms influence memory acquisition and recall by affecting hippocampal plasticity.