# The role of PI3Kg signaling in microglial dynamics and experience dependent synaptic plasticity

> **NIH NIH F30** · UNIVERSITY OF ROCHESTER · 2021 · $51,036

## Abstract

Project Summary:
Microglia, in addition to their role as immune cells of the central nervous system (CNS), are critical players in the
development and function of the CNS. Microglia are dynamic cells that interact extensively with neurons, allowing
them to regulate neurogenesis, refine neuronal networks, and influence synaptic plasticity. The same properties
that allow microglia to shape the development of the CNS may also lead to neurological disease if not properly
regulated. The extracellular signals that mediate microglial dynamics and interactions with neurons are not well
understood. Signaling through extracellular nucleotides has emerged as a key mechanism by which microglia
sense and interact with their external environment. Specifically, the microglial P2Y12 receptor is crucial for
microglial responsiveness to extracellular adenosine tri-phosphate (ATP) and mediates numerous microglial
functions, including ATP-dependent chemotaxis, microglia-neuron interactions, and experience-dependent
synaptic plasticity. However, little is known about the downstream signaling effectors that mediate these diverse
actions of P2Y12. My preliminary data and previously published work suggest that P2Y12 activates
phosphoinositide-3-kinase gamma (PI3Kγ), which in turn can activate the signaling pathways required for ATP-
mediated microglial chemotaxis. In this role, PI3Kγ could translate localized extracellular ATP signals into
directed microglial action and serve as a broad effector of P2Y12-dependent functions. In this proposal, I will
test the hypothesis that microglial PI3Kγ mediates microglial ATP-dependent chemotaxis, microglial dynamics,
and experience-dependent synaptic plasticity. In order to understand how PI3Kγ activation affects P2Y12-driven
microglial behavior, I will first determine the role of PI3Kγ in directed microglial motility towards ATP, using in
vitro, ex vivo, and in vivo approaches, and further dissect this molecular pathway, using a combination of
pharmacological and genetic manipulations (Aim 1). In parallel, I will determine how genetic loss of microglial
PI3Kγ affects microglial morphology, dynamics, and ocular dominance plastic in vivo, a process in which
microglia are known to participate. These two lines of investigation will examine the molecular pathways
underling distinct P2Y12-dependent microglia processes, and for the first time characterize the role of PI3Kγ in
the unperturbed CNS. Uncovering these molecular mechanisms will be critical to understanding the role of
microglia as mediators of neuronal function and their role in disease-related processes.

## Key facts

- **NIH application ID:** 10210217
- **Project number:** 5F30MH120974-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Brendan Steven Whitelaw
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210217

## Citation

> US National Institutes of Health, RePORTER application 10210217, The role of PI3Kg signaling in microglial dynamics and experience dependent synaptic plasticity (5F30MH120974-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210217. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*