# Mechanisms Underlying Cognitive Dysfuntion

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $457,639

## Abstract

ABSTRACT
Down syndrome (DS) is the most common genetic cause of intellectual disability and a huge biomedical
problem of increasing concern. Currently, there are no treatments that can prevent, delay, or restore deficits in
learning and memory associated with DS. Thus, the identification of novel neuronal targets for the
development of pharmacotherapies to treat memory decline associated with DS is an important goal.
 It has been hypothesized that alterations in protein synthesis (mRNA translation) could contribute to the
molecular, synaptic, and behavioral abnormalities of neurodevelopmental disorders, but whether dysfunctional
protein synthesis is responsible for the DS pathology remains unknown. The goal of this competing renewal is
to identify and correct the aberrant translational control program underlying DS pathophysiology. We focus on
protein synthesis controlled by the PKR-eIF2α signaling pathway because a) our preliminary findings indicate
that PKR-eIF2α signaling is selectively perturbed in the DS brain, and b) during the previous funding period,
we discovered PKR-eIF2α signaling as a central mechanism regulating not only the formation of long-term
memory, but also the two major and opposing forms of synaptic plasticity in the brain. We will combine
genetics, state-of-the-art intersectional molecular genetic approaches, pharmacology, electrophysiology, cell-
type-specific manipulation, genomics, and behavior to define the translational and synaptic plasticity
mechanisms underlying cognitive deficits in Down syndrome. We anticipate that the results of these Aims will
provide new fundamental insights into the biological basis of intellectual disability and could open avenues for
new therapies.

## Key facts

- **NIH application ID:** 9935172
- **Project number:** 5R01NS076708-09
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Mauro Costa-Mattioli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,639
- **Award type:** 5
- **Project period:** 2012-03-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935172

## Citation

> US National Institutes of Health, RePORTER application 9935172, Mechanisms Underlying Cognitive Dysfuntion (5R01NS076708-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9935172. Licensed CC0.

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