Neurotransmitter release is tightly regulated to ensure stability of neural circuits and reliability of synaptic transmission. At the Drosophila neuromuscular junction (NMJ), loss of postsynaptic glutamate receptor sensitivity triggers a retrograde signal that promotes presynaptic release of glutamate. Recently, our laboratory has shown that acute fasting of Drosophila larvae suppresses this retrograde signal. This nutrient dependent regulation of retrograde synaptic compensation depends on postsynaptic transcription of eukaryotic translation initiation factor 4E binding protein (4E-BP) to limit protein translation. This finding suggests nutrition and protein translation play significant roles in regulating the set point of synaptic function. In preliminary findings, we provide evidence to indicate this fasting response in the muscle depends on insulin signaling: phosphorylation of Akt, a target of insulin signaling, decreases with fasting in the muscle and overexpression of a constitutively active insulin receptor in the muscle protects against the inhibitory effects of fasting. We show that insulin peptide from the fat body is sufficient to suppress the muscle-derived retrograde signal to suggest signaling from fat bodies mediate the inhibitory fasting response at the NMJ. To extend our initial findings on acute fasting, we attempted to limit protein translation by exposing larvae to an amino acid deprived environment. To our surprise, we find that retrograde synaptic compensation remains intact. We hypothesize the amino acid sensor, general control non-derepressible-2 (GCN2), is activated during amino acid deprivation to maintain synaptic transmission. Indeed, we find that postsynaptic GCN2 is required to maintain baseline synaptic transmission in response to acute amino acid deprivation and this depends on phosphorylation of eukaryotic initiation factor 2A (eIF2?). Both our data on the effects of acute fasting and amino acid deprivation suggest the importance of protein translation in regulating synaptic transmission. We extend our investigation to additional proteins that may regulate synaptic transmission through translational mechanisms. We previously showed that leucine-rich kinase 2 (LRRK2) is important for regulating translation initiation and retrograde synaptic compensation. However, it remains unclear how LRRK2 may regulate protein translation. Here, we show that LRRK2 mediates the addition of eIF4A into the cap-binding complex for promoting the translation of specific mRNAs to activate retrograde synaptic compensation. Based on sound scientific premise and rigorous evaluation of our findings, we have built a proposal to uncover new modes in the regulation of synaptic transmission and further enrich our understanding of the molecular control of synaptic function.

Public Health Relevance

Accumulating experimental evidence suggests that a number of signaling pathways have to work in concert in order to fine tune synaptic function in neural circuits. We are particularly interested in how intracellular and extracellular molecular cues are integrated at the synapse. Our proposed studies are designed to extend our understanding of how metabolic signals are integrated by postsynaptic translational mechanisms, allowing for retrograde regulation of synaptic strength under normal and stressful biological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082793-08
Application #
9924669
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Miller, Daniel L
Project Start
2013-07-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
Liao, Edward H; Gray, Lindsay; Tsurudome, Kazuya et al. (2018) Kinesin Khc-73/KIF13B modulates retrograde BMP signaling by influencing endosomal dynamics at the Drosophila neuromuscular junction. PLoS Genet 14:e1007184
Kauwe, Grant; Tsurudome, Kazuya; Penney, Jay et al. (2016) Acute Fasting Regulates Retrograde Synaptic Enhancement through a 4E-BP-Dependent Mechanism. Neuron 92:1204-1212
Penney, Jay; Tsurudome, Kazuya; Liao, Edward H et al. (2016) LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction. Nat Commun 7:12188