# Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

> **NIH NIH R56** · CHILDREN'S RESEARCH INSTITUTE · 2024 · $399,987

## Abstract

Abstract
This project delves into the comprehensive study of the long-term neurobehavioral and cognitive impacts caused
by Prenatal Alcohol Exposure (PAE), aiming to shed light on potential therapeutic targets for Fetal Alcohol
Spectrum Disorders (FASD). During the previous funding period, crucial discoveries were made, particularly the
correlation between elevated levels of the potassium channel KCNN2 in the motor cortex and motor learning
deficits in PAE mice. Pharmacological interventions targeting KCNN2 showed promising improvements in these
learning deficits. Further investigations revealed significant alterations in the expression of Apolipoprotein E
(APOE) in both the cortex of PAE mice and the plasma of human PAE children. A specific single nucleotide
polymorphism (SNP) in the enhancer of APOE was identified as a potential risk factor for cognitive deficits in
human PAE subjects. Preliminary data suggested that postnatal administration of an APOE mimetic peptide
could mitigate motor learning deficits in PAE mice, and this effect was associated with the restoration of KCNN2
levels, adjustments in NMDAR decay time, and reduced phosphorylation of CREB. The hypothesis of this project
posits that dysregulated APOE expression in the brain contributes significantly to learning deficits observed in
FASD, and that treatment with APOE mimetics can alleviate these deficits. To validate and further explore this
hypothesis, the project is structured into three main objectives: 1. Understanding the underlying mechanisms
leading to reduced APOE expression in the cortex of PAE mice; 2. Identifying how decreased APOE levels
translate to learning and cognitive deficits in PAE mice; 3. Evaluating the effectiveness of APOE mimetic
treatment in improving learning and cognitive abnormalities in PAE mice. Through this multifaceted approach,
the project aims to contribute valuable insights to the field of neuroscience, specifically in understanding and
potentially treating the neurobehavioral sequelae of PAE and FASD.

## Key facts

- **NIH application ID:** 11193149
- **Project number:** 2R56AA026272-06
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Kazue Hashimoto-Torii
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,987
- **Award type:** 2
- **Project period:** 2019-01-25 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11193149

## Citation

> US National Institutes of Health, RePORTER application 11193149, Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders (2R56AA026272-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/11193149. Licensed CC0.

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