# CaMKII hypo-nitrosylatlon In age-related decline of synaptic plasticity and cognition

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2021 · $35,496

## Abstract

PROJECT SUMMARY
Synaptic plasticity, specifically long-term potentiation (LTP), is thought to underlie learning, memory, and
cognition. This function is disrupted in aging populations, where cognitive decline, such as forgetfulness and
decreased problem-solving capacity, is a well known impairment. LTP requires Ca2+/calmodulin (CaM)-
dependent protein kinase II (CaMKII), its Ca2+-independent autonomous activity and regulated binding to N-
methyl-D-aspartate receptor (NMDAR), which results in CaMKII translocation to excitatory synapses. It has
recently been suggested that hypo-nitrosylation may underlie the cognitive impairment seen in aging. My
preliminary live-imaging data demonstrate that application of an NO donor is sufficient to stimulate CaMKII
translocation to excitatory synapses and that this effect is abolished in a genetically modified knock-in mouse
line, CaMKIIΔSNO, in which CaMKII is rendered un-nitrosylable. Other preliminary data from the lab suggests that
these mice demonstrate normal high frequency stimulation (HFS)-induced LTP, but have impaired theta burst
stimulation (TBS)-induced LTP, which mimics what is seen in aged animals. My proposal will test the hypotheses
that (i) CaMKII synaptic targeting can be regulated by nitrosylation and (ii) CaMKII hypo-nitrosylation mediates
both age-related LTP and cognitive impairment. Specifically, I will use live-imaging, biochemical,
electrophysiological, and behavioral techniques on wild-type and mutant mice to determine the effect of CaMKII
nitrosylation on synaptic plasticity and determine if hypo-nitrosylation underlies cognitive impairment seen in
aging. Notably, this project utilizes intrabodies, which allow for simultaneous imaging of multiple endogenous
proteins without the normal confounds seen in protein overexpression experiments, to live-monitor endogenous
CaMKII targeting and an unpublished mouse line, CaMKIIΔSNO. Further, this project will provide a comprehensive
investigation of the role of CaMKII nitrosylation in synaptic plasticity and aging, as it begins at the molecular level
and proceeds through to functional behavioral outputs. The results from this project will not only elucidate the
cellular and molecular role of CaMKII nitrosylation in synaptic plasticity, but also provide insights into how hypo-
nitrosylation may underlie the cognitive impairment seen in aging, thus leading to a better understanding of
synaptic plasticity and potential therapeutic interventions for aging populations.

## Key facts

- **NIH application ID:** 10154827
- **Project number:** 1F31AG069458-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Nicole Rumian
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $35,496
- **Award type:** 1
- **Project period:** 2021-03-05 → 2023-03-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154827

## Citation

> US National Institutes of Health, RePORTER application 10154827, CaMKII hypo-nitrosylatlon In age-related decline of synaptic plasticity and cognition (1F31AG069458-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10154827. Licensed CC0.

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