Lithium prevents aberrant NMDA-induced F-actin reorganization in neurons.

Abstract

Increasing evidence suggests that cellular stress may underlie mood disorders such as bipolar disorder and major depression, particularly as lithium and its targets can protect against neuronal cell death. Here we describe N-methyl-D-aspartate (NMDA)-induced filamentous actin reorganization (NIFAR) as a useful in-vitro model for studying acute neurocellular stress and investigating the effects of mood stabilizers. Brief incubation of cultured neurons with NMDA (50 µM, 5 min) induces marked reorganization of F-actin within the somatodendritic domain of a majority of neurons. During NIFAR, F-actin is rapidly depleted from dendritic spines and aberrantly aggregates within the dendrite shaft. The widely used mood stabilizer lithium chloride prevented NIFAR in a time-dependent and dose-dependent manner, consistent with its known efficacy in treating bipolar disorder. Inhibitors of the lithium target glycogen synthase kinase 3 and its upstream activator phosphoinositide-3-kinase also prevented NIFAR. The antidepressant compounds imipramine and fluoxetine also attenuated NIFAR. These findings have potential relevance to neuropsychiatric diseases characterized by excessive glutamate receptor activity and synaptotoxicity. We propose that protection of the dendritic actin cytoskeleton may be a common mechanism shared by various mood stabilizers.

• Authors: Barbara Calabrese, Shelley Halpain
• Journal: Neuroreport (Neuroreport) Vol. 25 Issue 17 Pg. 1331-7 (Dec 03 2014) ISSN: 1473-558X [Electronic] England
• PMID: 25304495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Actins
• Antidepressive Agents
• Antipsychotic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Fluoxetine
• N-Methylaspartate
• Phosphatidylinositol 3-Kinase
• Glycogen Synthase Kinase 3
• Lithium Chloride
• Imipramine

Topics

• Actins (metabolism)
• Animals
• Antidepressive Agents (pharmacology)
• Antipsychotic Agents (pharmacology)
• Cells, Cultured
• Cytoskeleton (drug effects, physiology)
• Dendrites (drug effects, physiology)
• Dose-Response Relationship, Drug
• Fluoxetine (pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Hippocampus (drug effects, physiology)
• Imipramine (pharmacology)
• Lithium Chloride (pharmacology)
• N-Methylaspartate (metabolism)
• Neurons (drug effects, physiology)
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Time Factors