# Retrograde Regulation of Synaptic Strength by Translational Mechanisms

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $528,177

## Abstract

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 (eIF2α). 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.

## Key facts

- **NIH application ID:** 10151629
- **Project number:** 5R01NS082793-09
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Ali Pejmun Haghighi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $528,177
- **Award type:** 5
- **Project period:** 2013-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151629

## Citation

> US National Institutes of Health, RePORTER application 10151629, Retrograde Regulation of Synaptic Strength by Translational Mechanisms (5R01NS082793-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10151629. Licensed CC0.

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