Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity

Abstract

Any adult who has tried to take up the piano or learn a new language is faced with the sobering realization that acquiring such skills is more challenging as an adult than as a child. Neuronal plasticity, or the malleability of brain circuits, declines with age. Young neurons tend to be more adaptable and can alter the size and strength of their connections more readily than can old neurons. Myriad circuit- and synapse-level mechanisms that shape plasticity have been identified. Yet, molecular mechanisms setting the overall competence of young neurons for distinct forms of plasticity remain largely obscure. Recent studies indicate evolutionarily conserved roles for FoxO proteins in establishing the capacity for cell-fate, morphological, and synaptic plasticity in neurons.

Keywords: Daf-16; FoxO; microtubule dynamics; neurodegeneration; neuronal plasticity; synaptic plasticity.

Figure 1. FoxO transcription factors are evolutionarily-conserved regulators of neuronal form and function

Overview of neuronal FoxO functions in commonly studied model organisms.

Figure 2. Important cofactors that regulate neuron-specific FoxO functions

A) During neurogenesis, FoxO3 and ASCL1 share multiple target genes. In this context, FoxO3 inhibits ASCL1 transcriptional activity to promote neuronal stem cell quiescence. B) FoxO3 functions in the hippocampus where it is deacetylated by HDAC3. Deacetylation promotes FoxO3 localization to genes that are regulated by MeCP2 to control aspects of plasticity and behavior. C) In the cerebellar cortex, FoxO1 binds the SnoN1 transcription factor to regulate granule neuron migration. D) Daf-16 serves neuroprotective functions though a direct interaction with β-catenin in oxidatively-stressed C. elegans neurons.

Figure 3. Neuronal FoxOs enable morphological plasticity

A) dFoxO modulates axonal microtubule dynamics necessary for activity-dependent structural plasticity via transcriptional repression of the mitotic kinesin Pav-KLP. B) dFoxO regulates dendrite plasticity by promoting anterograde microtubule polymerization and overall microtubule network dynamics. C) FoxO1/3/6 regulate neuronal polarization and axon growth through the Pak1 kinase. D) Daf-16 promotes axonal outgrowth of developing AIY interneurons in C. elegans.

Figure 4. dFoxO acts in distinct molecular pathways in developing and adult motoneurons to promote synaptic function

A) In developing motoneurons, homeostatic regulation of neuronal activity occurs when high levels of synaptic glutamate feeds back onto presynaptic mGluRA receptors to downregulate neuronal excitability. Here, mGluRA signals via PI3K to promote Akt-dependent inhibition of dFoxO resulting in decreased motoneuron activity. B) Adult CM9 motoneurons exhibit a type of diet-induced synaptic plasticity whereby a high-calorie diet leads to decreased neurotransmitter release. Increased caloric intake activates Insulin signaling which functions to inhibit dFoxO’s transcriptional regulatory ability. Inhibited dFoxO function causes decreased expression of its transcriptional target, 4e-BP. As a result, 4e-BP is unable to inhibit translation of Complexin, a protein that acts to diminish synaptic vesicle release.