# Glial roles in experience-dependent critical period remodeling

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $407,869

## Abstract

Title: Glial roles in experience-dependent critical period remodeling
Summary
We propose glia actively prune brain circuits to optimize connectivity based on early-life sensory experience.
Drosophila approaches are used to identify molecular mechanisms of activity-dependent glial pruning restricted
to this short critical period. We propose these glial mechanisms go awry in several newly-linked disease states
of intellectual and autism spectrum disorders, including Fragile X syndrome (FXS), Noonan syndrome (NS),
LEOPARD syndrome (i.e. NS with Multiple Lentigines; NSML), and Neurobeachin (NBEA) associated autism
spectrum disorder (ASD). Our plan is to test the role of glia in experience-dependent circuit pruning in normal
and disease states, and to order glial mechanisms of recruitment, infiltration, engulfment and phagocytosis. We
employ targeted CRISPR knockout, conditional gene manipulations, and transgenic brain circuit connectivity
mapping to dissect neuron-to-glia signaling and glia function in this sensory experience-dependent remodeling.
We use timed olfactory cues to activate odorant receptor neurons, downstream projection neurons, and central
learning/memory center Kenyon cells, to test glial phagocytosis activity during and following the critical period.
In Aim 1, we block glial phagocytic function at multiple levels to test experience-dependent connectivity pruning
throughout this defined brain circuitry. We use transgenic single neuron synaptic labeling to visualize glial
phagocytosis via transmission electron microscopy. To test downstream activity-dependent mechanisms, we
use both excitatory and inhibitory optogenetic tools, as well as transgenic blockage of neurotransmission, in
hierarchical circuit studies of synaptic connectivity is sequential brain neuropils. This aim systematically tests
glial pruning in normal juvenile brains. In Aim 2, we dissect glia-specific Fragile X Mental Retardation Protein
(FMRP) roles in experience-dependent brain circuit pruning. We assay FMRP requirements in glial infiltration
phagocytosis using combined light microscopy and ultrastructural imaging. We test the FMRP-dependent
neuron-to-glia signaling mechanisms of glial recruitment and phagocytosis during experience-dependent circuit
remodeling. This work distinguishes FMRP roles within glia and neurons to understand FXS disease model
impairments in critical period brain circuit remodeling. In Aim 3, we test the roles of FMRP translational targets,
and consequent regulation of PKA/ERK signaling pathways. We test roles of 1) the direct FMRP mRNA target
Rugose/NBEA causative in autism spectrum disorder, which acts as a regulatory PKA anchor, and 2) the direct
FMRP mRNA target Corkscrew/SHP2 causative in the two Noonan syndromes of intellectual disability, which
is an ERK pathway regulatory phosphatase. We use separation of phases-based activity reporter of kinase
(SPARK) biosensors to image experience-dependent PKA/ERK signaling during the early-life c...

## Key facts

- **NIH application ID:** 10878362
- **Project number:** 1R01NS132867-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Kendal Broadie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $407,869
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878362

## Citation

> US National Institutes of Health, RePORTER application 10878362, Glial roles in experience-dependent critical period remodeling (1R01NS132867-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10878362. Licensed CC0.

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