# microRNA-Mediated Mechanisms Essential for the Structural Plasticity of Drosophila Glutamatergic Synapses

> **NIH NIH R56** · HARVARD MEDICAL SCHOOL · 2022 · $593,250

## Abstract

PROJECT SUMMARY / ABSTRACT
 The molecular and cellular mechanisms underlying the plasticity of excitatory synapses have fascinated
biologists for many decades. In addition to the importance of these processes in the acquisition and storage of
memories, as well as other adaptations of neural circuits to sensory input or other changing conditions, many of
the effector genes that participate in such mechanisms have recently been associated with a wide range of
neurological, psychiatric and other disorders of the human nervous system. Thus, it is little surprise that synapse
formation, plasticity and structural remodeling are under tight control at many levels. To better understand this,
we have investigated small, non-coding microRNA genes that serve as versatile yet selective regulators of
dynamic gene expression changes that underly the morphological plasticity of the synapse. Through multiple
rounds of genetic tool development, screening, and tissue-specific analysis, we have identified several highly
conserved microRNAs that are required in the postsynaptic cell to allow coordinated remodeling of the synapse
in response to acute stimulation. Because each microRNA controls the expression of specific target mRNAs, our
studies have led us to several key proteins whose expression must be downregulated to allow synapse
remodeling. In particular, our unpublished analysis of miR-219 suggests that it controls expression of a guanine
nucleotide exchange factor (GEF) specific to the Ral GTPase. Although this GEF (dRalGPS) is very highly
conserved, there are no peer reviewed publications on the Drosophila ortholog. Moreover, while fly miR-219 is
perfectly conserved with human miR-219a, and the miR-219 response element (MRE) in RalGPS is also
conserved across species, this relationship has escaped study by other labs. Prior work on Ral at the Drosophila
larval neuromuscular junction (NMJ) delineated a postsynaptic pathway that mediates morphogenesis of a
dendritic-spine like membrane array called the subsynaptic reticulum (SSR) by recruiting Sec5 and other Exocyst
components in response to neural activity. Analysis of our unpublished null mutation, expression transgenes,
and antibodies against dRalGPS show that, like Ral, this Ral GEF is both necessary and sufficient to control the
postsynaptic recruitment of key determinants of SSR structure. These and other observations described in this
proposal suggest a working model where synapse plasticity depends on convergent microRNA regulation of
dRalGPS and other effectors to reprogram the synaptic proteome for synapse addition rather than stability. We
propose to rigorously test this model with a combination of site-directed mutagenesis and tissue-specific analysis
(Aim 1), genetic epistasis and protein localization studies (Aim 2), and thorough regulatory analysis of the target
genes to address their dependence on miR-219 and other postsynaptic microRNA activities (Aim 3).

## Key facts

- **NIH application ID:** 10701428
- **Project number:** 1R56NS124811-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** David L. Van Vactor
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $593,250
- **Award type:** 1
- **Project period:** 2022-09-27 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701428

## Citation

> US National Institutes of Health, RePORTER application 10701428, microRNA-Mediated Mechanisms Essential for the Structural Plasticity of Drosophila Glutamatergic Synapses (1R56NS124811-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10701428. Licensed CC0.

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