Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

Area of Science:

• Neuroscience
• Pharmacology
• Metabolic Disorders

Background:

• Metformin, a common antidiabetic medication, is associated with reduced anxiety in patients, but the underlying mechanisms are unknown.
• Anxiety disorders are linked to specific neurobiological changes, including alterations in brain activity and neurotransmission.

Purpose of the Study:

• To investigate the role of AMP-activated protein kinase (AMPK) in the medial prefrontal cortex (mPFC) in anxiety-like behaviors.
• To elucidate the mechanism by which metformin exerts anxiolytic effects, focusing on AMPK and GABAergic signaling.

Main Methods:

• Utilized transgenic mouse models with brain-specific and GABAergic neuron-specific AMPK knockout.
• Administered metformin and employed genetic manipulation (overexpression/knockout) to modulate AMPK activity in the mPFC.
• Performed electrophysiological recordings (brain slice) to assess GABAergic transmission in mPFC pyramidal neurons.
• Evaluated anxiety-like behaviors using established behavioral paradigms.

Main Results:

• Anxiety induction led to region-specific AMPK reduction in the mPFC, correlating with anxiety-like behaviors.
• Metformin treatment or AMPK overexpression normalized mPFC AMPK activity and alleviated anxiety.
• Genetic deletion of AMPK in the mPFC induced anxiety and blocked metformin's anxiolytic effects.
• Metformin and AMPK activation restored GABAergic inhibitory transmission and corrected the excitation-inhibition imbalance in the mPFC.

Conclusions:

• AMPK activation within mPFC inhibitory neurons is a key mechanism underlying metformin's anxiolytic effects.
• Metformin's therapeutic potential extends beyond diabetes, suggesting its utility in treating anxiety disorders.
• Targeting AMPK in the GABAergic system of the mPFC offers a novel therapeutic strategy for anxiety.