# MMP-9 activity modulates sharp wave ripple events in the zebrafish hippocampus leading to cognitive deficits

> **NIH NIH F31** · GEORGETOWN UNIVERSITY · 2022 · $26,366

## Abstract

PROJECT SUMMARY/ABSTRACT
Over 300 million people worldwide and 17% of the United States population suffer from Major
Depressive Disorder (MDD), a heterogenous and recurrent disorder with no cure. MDD is considered the
leading cause of disability worldwide with hippocampal-dependent memory impairments as a symptom. These
memories rely on the finely tuned interplay between glutamatergic principal cells (PC) and GABAergic
parvalbumin positive (PV+) interneurons that give rise to sharp wave ripple (SWR) events. SWR events are
fast oscillations (129-220 Hz) associated with the compressed replay of awake memory traces
that are
sensitive to modulations in the structure and/or firing of these neurons.
Patients suffering from MDD exhibit a decreased hippocampal volume associated with hippocampal
memory impairments. Animal models suggest that a decreased hippocampal volume is the result of decreased
PC arborization and dendritic spine formation. PC simplification and an increase in PV+ interneurons will
destabilize the finely tuned hippocampal network, impairing SWR events, resulting in hippocampal memory
impairments.
Antidepressant treatment, though effective in less than 70% of diagnosed patients, increases PC
arborization and dendritic spine formation and potentially decreases PV+ interneuron firing, leading to an
increase in SWR events and better cognitive performance.
Previous work from my laboratory has shown that the increase in SWRs after antidepressant treatment
was matrix metalloproteinase-9 (MMP-9) dependent, a gelatinase involved in the remodeling of the
extracellular matrix. However, a direct link between MMP-9 activity and modulation of SWRs through changes
in PCs and PV+ neurons is yet to be made. This F31 proposal requesting 2 years of support encompasses two
main aims. Aim 1 will test the hypothesis that MMP-9 inhibition leads to a decrease in SWR events associated
with impaired hippocampal memory consolidation. Aim 2 will investigate how MMP-9 inhibition leads to a
decrease in SWR events by focusing on 1) the specific biochemical and structural changes in PCs that
modulate their excitability (e.g., arborization, dendritic formation) and 2) changes in PV+ excitability using
zebrafish. Preliminary data shows that decreasing MMP-9 activity decreases SWR events in the hippocampus
of zebrafish using ex vivo whole-brain Local Field Potential (LFP) recordings.
This multidisciplinary research will advance the field of neuroscience by uncovering some of the
mechanisms involved in the onset and progression of MDD postulating zebrafish as a tool to screen for novel
antidepressants/MMP-9 modulators. It will also enhance our knowledge in the circuitry involved in SWR
development.

## Key facts

- **NIH application ID:** 10386410
- **Project number:** 1F31MH129061-01
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Ismary Blanco
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $26,366
- **Award type:** 1
- **Project period:** 2022-01-01 → 2022-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386410

## Citation

> US National Institutes of Health, RePORTER application 10386410, MMP-9 activity modulates sharp wave ripple events in the zebrafish hippocampus leading to cognitive deficits (1F31MH129061-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386410. Licensed CC0.

---

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