# Impact of histamine H3 receptor agents on PAE-induced synaptic plasticity deficits in dentate gyrus

> **NIH NIH P50** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $308,485

## Abstract

PROJECT SUMMARY
Learning disabilities are the most common behavioral deficit observed in patients with Fetal Alcohol Spectrum
Disorder (FASD). Currently, there are no established clinically effective pharmacotherapeutic interventions for
these behavioral problems. Using a well-established rat model of FASD, we have reported that the histamine
H3 receptor inverse agonist / antagonist ABT-239 ameliorates prenatal alcohol exposure (PAE)-induced deficits
in synaptic plasticity and learning. We have also observed increased H3 receptor-effector coupling and a
heightened H3 receptor-mediated inhibition of the probability of glutamate release in dentate gyrus of PAE rats.
Collectively, these results suggest that PAE increases H3 receptor-mediated inhibition of glutamate release and
that ABT-239 reduces this heightened inhibitory influence. One parsimonious explanation for why PAE rats are
more sensitive to H3 receptor agents is a PAE-induced increase in the expression of the rH3A isoform of
histamine H3 receptors relative to the rH3C isoform. This putative shift would confer greater sensitivity to the
inhibitory effects of histamine H3 receptor agonists in PAE rats. The principal objectives of this NMARC research
component application are to: 1) Examine whether PAE increases the expression of rH3A relative to rH3C in
entorhinal cortical neurons projecting to the dentate gyrus. 2) More thoroughly establish the consequences of a
PAE-induced elevation in H3 receptor-effector coupling and the effects of second H3 receptor inverse agonist /
antagonist namely, SAR152954, on H3 receptor-mediated inhibition of glutamatergic neurotransmission in
dentate gyrus. In Specific Aim 1A, we will employ in situ hybridization and qRT-PCR approaches to first confirm
whether PAE increases the rH3A/rH3C mRNA expression ratio. In Aim 1B, we will use a [35S]-GTPS binding
assay in histological sections to conduct a more detailed examination of the effects of PAE on H3 receptor-
effector coupling and assess the differential sensitivity of PAE rats to SAR152954 relative to controls. In Specific
Aim 2A, we will conduct in vitro slice physiology studies to examine: 1) The impact of PAE on the effects of the
H3 receptor agonist methimepip on fEPSP responses and pair-pulse plasticity in dentate gyrus, under baseline
and after theta burst stimulation conditions. 2) The effects of SAR152954 alone and in the presence of
methimepip on paired-pulse ratio and long-term potentiation. In Aim 2B, we will examine the impact of PAE on
fEPSP and PPR before and after high frequency stimulations in awake freely moving rats. We predict that
SAR152954 will ameliorate the heightened H3 receptor mediated inhibition of synaptic plasticity in PAE rats at
concentrations/doses that do not impair synaptic transmission in control rats. These studies address two of the
three strategic objectives of NMARC, namely advancing our understanding of the neurobiological consequences
of PAE, as well as working toward...

## Key facts

- **NIH application ID:** 10207335
- **Project number:** 5P50AA022534-08
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Daniel D. Savage
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $308,485
- **Award type:** 5
- **Project period:** 2014-08-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207335

## Citation

> US National Institutes of Health, RePORTER application 10207335, Impact of histamine H3 receptor agents on PAE-induced synaptic plasticity deficits in dentate gyrus (5P50AA022534-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10207335. Licensed CC0.

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