# The role of neuronal activity on retinal angiogenesis and blood-retina barrier (BRB) maturation

> **NIH NIH K99** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $133,958

## Abstract

PROJECT SUMMARY
Reciprocal interactions among neuroglial and vascular components of the postnatal retina are critical for proper
angiogenesis and the establishment of the blood-retinal barrier (BRB). Although neuronal or glial cells-derived
signals that promote angiogenesis and BRB maturation are being elucidated, we still do not understand: a) how
neuronal synaptic activity in the retina influences these processes; b) which neurotransmitter(s) contribute to
these processes; and c) whether neurotransmitters act on endothelial cells (ECs) directly or indirectly, via
astrocytes or Müller cells. The superficial plexus vasculature develops (P1-P8) during the spontaneous
cholinergic wave of neural activity (P0-P10) and photoactivation of Opn4+ retinal ganglion cells (RGC). In
contrast, the deep plexus vasculature and BRB development span cholinergic and glutamatergic waves of neural
activity (P10-P14), glutamatergic synaptic activity of photoreceptors (P10 onwards) as well as photoactivation of
Opn4+ RGCs. Transient pharmacological blockade of cholinergic wave impairs deep plexus angiogenesis and
BRB maturation; however, the role of extracellular glutamate in these processes is unknown. In preliminary
findings, we have primarily used three mouse strains to assess the effects of synaptic glutamate release on
retinal angiogenesis and the BRB: a) Vglut1 -/-, that lack glutamate release, b) Gnat1-/-, in which rod
photoreceptors remain depolarized, thus release excess glutamate, and c) Chrnb2-/-, where cholinergic wave is
abolished and glutamatergic wave begins early (P8). We have found that synaptic glutamate release is a positive
regulator of deep plexus angiogenesis and BRB maturation. This effect is mediated by inducing expression of
Norrin in Müller glia and Norrin/b-catenin pathway activation in ECs. Based on these preliminary data, we
hypothesize that released glutamate levels are sensed by Müller cells, which in turn operate as transducers to
induce expression of angiogenic and BRB-forming factors and promote deep plexus angiogenesis and BRB
maturation. We will test this hypothesis through three aims. First, we will examine how modulation of glutamate
levels [Vglut1-/- mice (no glutamate release), Gnat1-/- mice (high glutamate release), and Chrnb2-/- mice (early
onset of glutamatergic wave)] regulates retinal angiogenesis and structural and functional BRB integrity. Next,
we will determine whether Müller cells respond to extracellular glutamate levels by inducing expression of
angiogenic and barriergenic factors. We will examine Müller cell response [cell number, expression of GLAST
(Slc1a3; a major glutamate transporter), glutamine synthetase (enzyme responsible for converting glutamate to
glutamine) and Norrin (the major Wnt ligand expressed by Müller cells)] in Vglut1-/-, Gnat1-/- and Chrnb2-/- mice.
Finally, we will test if activation of endothelial Norrin/b-catenin signalling that promotes angiogenesis and BRB
maturation can rescue deficits in...

## Key facts

- **NIH application ID:** 10834156
- **Project number:** 5K99EY033909-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Saptarshi Biswas
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $133,958
- **Award type:** 5
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834156

## Citation

> US National Institutes of Health, RePORTER application 10834156, The role of neuronal activity on retinal angiogenesis and blood-retina barrier (BRB) maturation (5K99EY033909-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10834156. Licensed CC0.

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