AMPK activation regulates neuronal structure in developing hippocampal neurons

• AMPK subunits upregulated during neuronal development.
• Knockout of either AMPK catalytic subunit does not affect basal axon or dendrite growth.
• Activation of AMPK during development impairs axogenesis and dendrite growth and arborization.
• Activation of AMPK inhibits the positive regulators of dendritic growth Akt and mTOR.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a cellular and whole organism energy sensor to regulate ATP-consuming (anabolic) and ATP-generating (catabolic) pathways. The heterotrimeric AMPK complex consists of a catalytic α-subunit, regulatory β-subunit, and an AMP/ATP-binding γ-subunit. Several alternate isoforms exist for each subunit (α1, α2, β1, β2, γ1, γ2 and γ3). However, little is known of the expression pattern or function of the individual catalytic complexes in regulating neuronal structure. In this study, we examined the role of AMPK subunits in differentiating hippocampal neurons. We found that during development, the expression of AMPK subunits increase and that activation of AMPK by energetic stress inhibits neuronal development at multiple stages, not only during axon outgrowth, but also during dendrite growth and arborization. The presence of a single functional AMPK catalytic complex was sufficient to mediate these inhibitory effects of energetic stress. Activation of AMPK mediates these effects by suppressing both the mTOR and Akt signaling pathways. These findings demonstrate that the energy-sensing AMPK pathway regulates neuronal structure in distinct regions of developing neurons at multiple stages of development.