# Role of Norrin in synaptic biology during development, adulthood, and disease

> **NIH NIH F32** · JOHNS HOPKINS UNIVERSITY · 2021 · $66,390

## Abstract

PROJECT SUMMARY
Neuronal synaptic connections are essential for executing the distinct tasks that are required for brain
homeostasis and function. Disturbances to synaptic biology during development or in mature neuronal networks
are a key hallmark of most neurodevelopmental disorders and neurodegenerative diseases, respectively. Thus,
a better understanding of the mechanisms that govern the establishment and maintenance of synapses could
provide new insights into the origins of these disorders and potential therapeutic opportunities. Extra-neuronal
influences, whether via direct cellular contact or released proteins, have been demonstrated to be critical in
governing synaptic physiology. Outside of the broad metabolic responsibilities that astrocytes fulfill in the brain
during normal physiology, it is becoming increasingly clear that astrocytes are instrumental in modulating
neuronal synaptic connections. Specifically, astrocytic interactions with neuronal synapses are increasingly
implicated in 1) the establishment of proper synaptic connections and 2) dysfunctions that negatively impact
synaptic biology. Our group was the first to document the involvement of alternative Wnt ligand, Norrin, in
synaptic properties—a protein long associated with the X-linked genetic disorder Norrie Disease (ND). Namely,
Norrin enhanced neuronal firing frequency and network connectivity in in vitro cultures and caused synaptic
abnormalities in vivo in adult Norrin-null mice. However, the mechanistic basis of these findings remains
unknown, as well as whether Norrin is important in synaptogenesis. Thus, the overall goal of this proposal is
to define the role that Norrin plays in synaptic biology, including the establishment of these connections
during development and maintenance in adulthood. Additionally, this study will be the first to use a
humanized mouse model of ND to provide characterization of the inherent and synaptic properties of ND
cortical neurons. These objectives will be pursued with murine models, including Norrin-null mice and human
Norrin gene point mutation (V45E) mice. First, I will determine the physiological mechanism by which Norrin
mediates enhanced neuronal firing frequency and connectivity using whole-cell patch clamp electrophysiology
in in vitro and ex vivo preparations. Additionally, I will use molecular biology and imaging techniques to evaluate
Norrin’s effect on synaptic neurotransmitter receptor expression. Secondly, I will investigate the involvement of
Norrin in synaptogenesis by utilizing iDISCO, single-cell RNAseq, and RNAscope in the postnatal mouse brain.
Using the V45E mice I will characterize the electrophysiological properties of cortical neurons in the mature ND
brain. Lastly, utilizing high-content in vitro and in vivo imaging, real-time synaptic dynamics will be evaluated in
conditions of functional and dysfunctional Norrin across the synaptogenesis period. This proposal will provide
novel insights into Norrin-mediated ...

## Key facts

- **NIH application ID:** 10348333
- **Project number:** 1F32NS120940-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Emily G Thompson
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 1
- **Project period:** 2022-03-07 → 2025-06-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348333

## Citation

> US National Institutes of Health, RePORTER application 10348333, Role of Norrin in synaptic biology during development, adulthood, and disease (1F32NS120940-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10348333. Licensed CC0.

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