# Mechanisms of serotonin and serotonin receptor biology in normal and glaucomatous retinas

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $540,819

## Abstract

PROJECT SUMMARY
Glaucoma is a progressive disease of retinal ganglion cells (RGCs) and their axons. Some evidence suggests
that oral SSRIs (selective serotonin reuptake inhibitors), which increase serotonin (5-HT) levels, may have a
protective effect against progression of open angle glaucoma. To understand the mechanism of this potential
protection, we assessed RGC expression of serotonin receptors (HTRs) in mouse and human scRNA-seq
datasets. In mice, Htr1b is expressed in RGCs at a high level and preferentially expressed in alpha RGCs
(αRGCs). In humans, HTR1B is expressed in RGCs, suggesting a conserved function. In mouse retinal tissue,
we detected Htr1b transcript in the ganglion cell layer (GCL) and HTR1B protein in the GCL and inner plexiform
layer near excitatory post-synaptic sites. Using electroretinogram (ERG), optokinetic response (OKR), and
multielectrode array (MEA) testing in conjunction with histology in Htr1b-/- and control mice, we found that Htr1b-/-
retinas are anatomically normal, but Htr1b is required for several aspects of normal inner retinal function. We
also found that HTR1B agonists and antagonists impact ON and OFF RGCs differently. Finally, SSRI
administration in drinking water mitigated some IOP-induced phenotypes without reducing IOP. These data
suggest that 5-HT and HTRs play a previously unrecognized role in RGC function and IOP/glaucoma
susceptibility. We will test the hypothesis that Htr1b is required for normal RGC and αRGC function and acts
through downstream effects on membrane excitability. We will also ask if increased 5-HT signaling through Htr1b
promotes RGC resistance to injury whereas decreased 5-HT signaling through Htr1b increases RGC
susceptibility in the setting of elevated IOP. There are three aims: (1) Determine the cell-type specific function of
Htr1b in the inner retina; (2) Elucidate the intracellular mechanisms of action of Htr1b in four αRGC subtypes;
and (3) Assess the impact of altered 5-HT signaling on glaucoma susceptibility. In Aim 1, we will combine a novel
conditional Htr1b knockout with Cre-expressing lines specific for RGCs, αRGCs, or amacrine cells to dissect
Htr1b function at the retinal circuitry level (ERG/MEA), behavioral level (OKR), and brain circuitry level (mapping
of RGC axon transport to the superior colliculus). We will also use a novel system of adult mouse RGC isolation
and culture to test cell-autonomous anatomic responses to 5-HT. In Aim 2, we will use pharmacologic techniques
alongside whole-cell patch clamp recording to compare 5-HT and Htr1b biology among the four αRGC subtypes
and to test the hypothesis that HTR1B acts via regulation of potassium channels. We will also use fibronectin
intrabodies generated with mRNA display to map HTR1B to excitatory and inhibitory post-synaptic sites. In Aim
3, we will provide SSRI in the drinking water of mice with elevated IOP and use both physiologic and anatomic
studies to determine if increased 5-HT causes RGC neuroprotecti...

## Key facts

- **NIH application ID:** 10985732
- **Project number:** 1R01EY035646-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Benjamin J Frankfort
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,819
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985732

## Citation

> US National Institutes of Health, RePORTER application 10985732, Mechanisms of serotonin and serotonin receptor biology in normal and glaucomatous retinas (1R01EY035646-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10985732. Licensed CC0.

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