PgmNr D1272: Neuronal insulin signaling negatively regulates synaptic vesicle exocytosis via a FOXO-dependent mechanism.

Authors:
Rebekah Mahoney 1,2 ; Jorge Azpurua 1 ; Benjamin Eaton 1,2


Institutes
1) UTHSCSA, San Antonio, TX; 2) Barshop Institute for Aging and Longevity, San Antonio, TX.


Keyword: synaptic function and organization

Abstract:

Altered insulin signaling within the brain has been linked to cognitive dysfunction and neurodegenerative disease. Appropriate signaling downstream of the insulin/IGF-1 receptor has been linked to a number of cell processes that could contribute to the effects of insulin signaling on brain function including maintenance of neuronal health, reduced cell stress, neuron development, and synapse function. However, a role for insulin signaling during the regulation of neurotransmission has not been demonstrated. Using a novel synaptic preparation in adult Drosophila, we have found that cell autonomous insulin signaling negatively regulates the presynaptic release of neurotransmitter via the activity of the eif-4e binding protein (4eBP), a negative regulator of protein translation. In this context, the activity of 4eBP is regulated transcriptionally by the forkhead transcription factor Foxo and not the mammalian target of rapamycin (mTOR). Furthermore, the regulation of neurotransmission by insulin signaling requires the mRNA binding protein Staufen, which is known to localize mRNAs to distinct compartments within neurons, and is blocked by the protein synthesis inhibitor cycloheximide. Our data supports the model that cell autonomous insulin signaling regulates the presynaptic release of neurotransmitter via the local translation of negative regulators of synaptic vesicle exocytosis. Analysis of candidate molecules required for the effect of insulin signaling on synaptic vesicle exocytosis will be presented.