# TRPM2 channels and synaptic dysfunction following ischemic injury in the developing brain.

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2021 · $189,320

## Abstract

Project Summary
Global cerebral ischemia caused by cardiac arrest results in many neurological sequelae, including deficits in
learning and memory. These deficits are as evident in children as they are in adults. The resulting neurological
sequelae from cardiac arrest (CA) in children likely arise from both neuronal death and altered physiology in
surviving neurons. TRPM2 channels are non-selective ion channels that are activated by hyperoxidative stress
and are compelling targets in preventing neurotoxicity and cellular dysfunction. Our lab has recently designed a
novel inhibitor of TRPM2 channels, known as tatM2NX, to better understand the role of TRPM2 in neuronal
death and dysfunction. A useful measure to assess neuronal dysfunction is to investigate the level of synaptic
function. The ability for neurons to undergo synaptic plasticity (long-term potentiation; LTP) in the hippocampus
is recognized as an innate measure of function and is a widely accepted cellular model for learning and
memory. This proposal makes use of a novel cardiac arrest model in juvenile mice (p21-25) to investigate the
hypothesis that activation of TRPM2 channels contributes to impairment of synaptic function and cognitive
deficits following global cerebral ischemia. We have found that inhibiting TRPM2 soon after juvenile CA leads
to preservation of synaptic function, despite no significant change in neuronal death. We will further test the
hypothesis by inhibiting TRPM2 at delayed time points (7-14 days after PCA). Inhibition of TRPM2 will be done
with pharmacology (in vivo tatM2NX) or genetic modulation (TRPM2-/-, lentiviral shRNA TRPM2 knockdown)
and function will be assessed by electrophysiology and behavior. Preliminary data suggest that delayed
inhibition of TRPM2 reverses synaptic impairments after CA. We will use signal transduction techniques to
identify the mechanism for synaptic impairment after ischemia-induced TRPM2 activation. We will focus on the
hypothesis that activation of TRPM2 signals calcineurin, leading to decreased synaptic function. Finally, we
have found that while ischemia in young animals results in impairment of synaptic function up to 14 days after
CA, there is remarkable endogenous recovery to control levels. The final aim of the project will investigate the
role of developmental changes in TRPM2 expression in neurons through puberty into adulthood that may
account for endogenous recovery of impaired synaptic function. Overall, this project has high translational
potential through the opportunity of redefining therapeutic windows after global cerebral ischemia in children.
Experiments outlined in this proposal will provide important training for an independent research career. In this
proposal, I will learn hippocampal lentivirus shRNA transfection, behavior testing, and signal transduction
techniques to assess protein expression and function. The mentor team assembled has experience and
expertise to assure completion of this project. Upon...

## Key facts

- **NIH application ID:** 10197230
- **Project number:** 5K08NS097586-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Robert M Dietz
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $189,320
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197230

## Citation

> US National Institutes of Health, RePORTER application 10197230, TRPM2 channels and synaptic dysfunction following ischemic injury in the developing brain. (5K08NS097586-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197230. Licensed CC0.

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