Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Disrupted in schizophrenia-1 (DISC1) is a crucial scaffolding protein implicated in psychiatric disorders.
• Mutations in DISC1 are linked to schizophrenia and major depressive disorder.
• DISC1 regulates neurite outgrowth and cortical development, interacting with glycogen synthase kinase-3β (GSK-3β).

Purpose of the Study:

• To investigate the impact of ketamine on DISC1 and GSK-3β expression.
• To explore the role of GSK-3β activity in ketamine-induced changes in DISC1.
• To determine if lithium, a GSK-3β antagonist, can mitigate ketamine's effects on DISC1 and neuronal growth.

Main Methods:

• Primary neuronal cell cultures from rat pups were treated with ketamine and lithium.
• Levels of DISC1, GSK-3β, and cleaved-caspase-3 were measured using immunoblots.
• DISC1-GSK-3β binding was assessed via co-immunoprecipitation.
• Neurite outgrowth was quantified by measuring axon and dendrite length.

Main Results:

• Ketamine decreased DISC1 levels and GSK-3β phosphorylation in a dose- and time-dependent manner, indicating increased GSK-3β activity.
• Lithium significantly attenuated ketamine's reduction of DISC1 levels.
• Ketamine reduced DISC1-GSK-3β co-immunoprecipitation and axonal length, effects reversed by lithium.

Conclusions:

• Acute ketamine administration decreases DISC1 levels and axonal growth.
• Lithium counteracts ketamine-induced decreases in DISC1 and promotes axonal growth.
• This study establishes a link between DISC1 modulation and ketamine-induced neurodegenerative effects.