# Astrocyte RNA degradation and cognitive function

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $540,850

## Abstract

PROJECT SUMMARY
Despite its putative link to many mental illnesses, Nonsense-Mediated mRNA Decay (NMD) represents a
relatively unexplored mechanism for regulating mRNA stability in brain function. NMD functions in a tissue-,
cell type- and cell-state specific manner and modulates stability of selective mRNAs to fine-tune transcript
abundance. There is dearth of knowledge regarding the identity of such NMD target RNAs, particularly in cells
in their normal in vivo context. A particularly large gap in the field is the cell-specific function and targets
of NMD in vivo. Our recent work has established that neuronal NMD regulates GLUR1 signaling and is
required for proper synaptic plasticity, cognition, and local protein synthesis in dendrites, providing fundamental
insight into the neuron-specific function of NMD within the brain. To date, no study has reported a specific
function for NMD nor identified NMD substrates within glial cells in the brain. Astroglial control of synaptic
activity translates into regulation of cognition making astrocytes a novel therapeutic target to treat cognitive
dysfunctions. However, the mechanisms through which astrocytes regulate neuronal function are not well
understood. Currently, it is not known whether mRNA degradation in astrocytes contribute to the regulation of
synaptic plasticity and behavior. The goal of this application is to determine the contribution of astrocytic
NMD to synaptic plasticity and cognitive performance. Several predicted ‘canonical’ and ‘atypical’ NMD
targets are expressed in astrocytes. Our gene ontology analysis of these predicted NMD targets identified
molecular function enrichment for Ca2+ signaling. Consistent with this, we have found that disruption of NMD in
astrocytes resulted in elevated Ca2+ activity in vitro. Dynamic Ca2+ transients in astrocytes have been
suggested to control proper basal synaptic transmission and modulate hippocampal LTP. We have also found
that conditional ablation of NMD in astrocytes impaired memory in the adult mice. Based on the published
literature and our preliminary studies, we hypothesize that NMD regulates Ca2+ activity in astrocytes, and
astrocytic NMD is required for proper cognitive function and behavior in the adult brain. To test this
hypothesis, we propose to determine 1) whether NMD is required for different aspects of learning and memory
2) the effects of astrocytic NMD ablation on neurons (e.g., assessing neuronal network connectivity and
synaptic plasticity) and 3) functional deficits of NMD-deficient astrocytes (i.e., by assessing Ca2+ activity in vivo)
and in vivo NMD targets in astrocytes. We will use a combination of techniques including an inducible-genetic
mouse model, behavioral assays, electrophysiology, live-animal Ca2+ imaging by two-photon microscopy,
stereotaxic viral labeling, Multielectrode Array Assay, in vivo RNAseq/bioinformatics, and in vivo HITS-CLIP.
The successful completion of this research will provide a coherent view of...

## Key facts

- **NIH application ID:** 10862808
- **Project number:** 5R01MH129797-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dilek Colak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,850
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862808

## Citation

> US National Institutes of Health, RePORTER application 10862808, Astrocyte RNA degradation and cognitive function (5R01MH129797-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862808. Licensed CC0.

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