Chronic lithium treatment antagonizes glutamate-induced decrease of phosphorylated CREB in neurons via reducing...

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Cyclic AMP response element binding protein (CREB) is crucial for adaptive synaptic responses and neuroprotection.
• CREB is implicated in antidepressant mechanisms and lithium's neuroprotective effects.
• Glutamate toxicity decreases CREB phosphorylation at serine(133) via N-methyl-D-aspartate (NMDA) receptors.

Purpose of the Study:

• To investigate the effects of acute and chronic lithium on cerebellar granule neurons exposed to toxic glutamate concentrations.
• To elucidate the molecular mechanisms underlying lithium's neuroprotective actions.
• To determine lithium's impact on CREB phosphorylation and CRE-driven gene expression under excitotoxic conditions.

Main Methods:

• Primary cultures of cerebellar granule neurons.
• Acute and chronic lithium treatments.
• Glutamate exposure to induce excitotoxicity.
• Analysis of CREB phosphorylation at serine(133).
• Transfection studies for CRE-driven gene expression.
• Pharmacological inhibition of protein phosphatase 1 and MEK pathways.

Main Results:

• Chronic, but not acute, lithium treatment prevented glutamate-induced decreases in phosphorylated CREB.
• Chronic lithium enhanced CRE-driven gene expression in the presence of glutamate.
• Glutamate-induced dephosphorylation of CREB is mediated by protein phosphatase 1.
• Chronic lithium decreased protein phosphatase 1 activity and increased MEK activity.
• MEK inhibition blocked lithium's effect on phosphorylated CREB.

Conclusions:

• Chronic lithium treatment preserves CREB phosphorylation during glutamate excitotoxicity.
• Lithium's neuroprotection is mediated by decreased protein phosphatase 1 and increased MEK activity.
• Enhanced CREB activity and downstream genes like bcl-2 likely contribute to lithium's neuronal survival effects.