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

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2022 · $401,623

## Abstract

Abstract:
Alzheimer’s disease (AD) is the most common cause of dementia and the most common neurodegenerative
disease. Apolipoprotein E (APOE) isoforms are known as a major risk factor of AD and dementia, while single
nucleotide polymorphisms (SNPs) in the non-coding regulatory surrounding regions of the transcription reduce
the levels of ApoE and the reduction is associated with the AD phenotypes. Despite crucial involvement of APOE
in the AD/dementia pathogenesis has been well established, there is still no available treatments targeting APOE.
 The goal of the parent R01 award (R01AA026272) is to reveal mechanisms by which prenatal alcohol
exposure (PAE) results in long-term impacts on the neurobehavior of offspring and find effective treatments for
the symptoms caused by such impacts in Fetal Alcohol Spectrum Disorders (FASD). Through the research
supported by this parent award, genome-wide chromatin accessibility was compared between control and PAE
mice with the neurons dissociated from motor cortex. One of the major changes that we found was in the locus
of ApoE. We also observed that the ApoE protein level is reduced in the motor cortex and plasma in postnatal
PAE mice, and that daily administration of an ApoE mimetic during postnatal day 20-30 can mitigate the motor
skill learning deficits in PAE mice. Interestingly, this treatment by the ApoE mimetic restored the level of
endogenous ApoE while reduced the expression of a calcium-activated potassium channel, Kcnn2 (Potassium
Calcium-Activated Channel Subfamily N Member 2), which is upregulated in the cerebral cortex of PAE mice
and contributes to the motor skill learning deficits, as we have reported recently. In our collaboration with NIAAA-
funded Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we also found that the SNP in
the distal enhancer of APOE was a potential risk factor of cognitive deficits in human PAE subjects.
 Involvement of altered KCNN2 in AD and other neurodegenerative diseases has been also reported in
many studies on human patients and animal models. A recent survey of 541 people with FASD in Canada and
the United States also has reported that the frequency of early onset dementia is 209 times higher in FASD
patients than in the general population, the underlying mechanisms of which remain unknown.
 Together, these lines of evidence suggest that PAE-mediated ApoE reduction (possibly by altered
chromatin accessibility at the ApoE locus, and it might be exacerbated by the SNP in the APOE enhancer)
contributes to learning disabilities and early onset dementia in FASD by involving the overproduction of KCNN2
in the cerebral cortex. In this supplementary project, we will first define whether the effect of ApoE replenishment
in improving learning ability of PAE mice is mediated by suppression of Kcnn2 upregulation. Then we will define
whether the suppression of Kcnn2 upregulation in PAE mice by ApoE replenishment is mediated by NMDAR.
Successful compl...

## Key facts

- **NIH application ID:** 10499021
- **Project number:** 3R01AA026272-04S1
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Kazue Hashimoto-Torii
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $401,623
- **Award type:** 3
- **Project period:** 2019-01-25 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499021

## Citation

> US National Institutes of Health, RePORTER application 10499021, Administrative Supplement: Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders (3R01AA026272-04S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10499021. Licensed CC0.

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