# Defining the interactions between microglia and synapses in brain development and disease

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $117,504

## Abstract

PROJECT SUMMARY/ ABSTRACT
Establishing precise synaptic connections is critical for normal brain function. Synaptic dysfunction can lead to
neuronal hyperexcitability, contributing to disorders including epilepsy. Microglia are the dominant immune cells
in the brain and play multiple roles in synaptic development, modulating neuronal excitability, and engulfing
excess excitatory synapses. However, the mechanisms by which microglia impact synapses have largely been
investigated with fixed tissue histology or in limited regions of the adult brain using rodent models. In fact,
microglial engulfment of whole synapses has not been directly observed in the developing brain. In this proposal,
I will use a zebrafish model system to study microglial-synapse interactions in the intact developing brain. My
recently published work identified a population of synapse-associated microglia (SAMs) enriched in the zebrafish
hindbrain and defined its transcriptional profile by single-cell and regional bulk sequencing. In this proposal, I will
examine this microglial subset using a combination of live imaging and candidate gene deletion in both
physiology and in the context of hyperexcitability. Aim 1 will determine if microglia engulf synapses during
development and the impact of immune activation or after deletion of a core lysosomal protease known as
cathepsin b (ctsba) - a top candidate from my transcriptomic work. Aim 2 will further assess these phenotypes
in the context of chemically induced hyperexcitability and use startle behavior recordings to assess the impact
on neural circuit function. Finally, in Aim 3 (R00 phase), I will define the molecular mechanisms regulating
lysosome activity during microglia phagocytosis and transcriptionally profile microglia following neuronal
hyperexcitability. Together these studies will open a distinct direction using a new model to identify molecular
pathways that regulate microglia-synaptic interactions with the potential to investigate non-neuronal therapeutic
interventions that impact development and disease states such as epilepsy.

## Key facts

- **NIH application ID:** 10740644
- **Project number:** 1K99NS130018-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Nicholas Jeremy Silva
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $117,504
- **Award type:** 1
- **Project period:** 2023-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740644

## Citation

> US National Institutes of Health, RePORTER application 10740644, Defining the interactions between microglia and synapses in brain development and disease (1K99NS130018-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10740644. Licensed CC0.

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