# Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

> **NIH NIH R01** · AUBURN UNIVERSITY AT AUBURN · 2021 · $290,671

## Abstract

Project Abstract
 Cannabis is one of the most illicit drugs used during pregnancy, and with increased legalization, use
during pregnancy is expected to rise. Clinical studies have shown prenatal cannabinoid exposure (PCE) results
in residual cognitive deficits in offspring. Despite the rise in PCE, there is little understanding of a
comprehensive mechanistic pathway responsible for learning and memory deficits associated with PCE. Our
long-range goal is to understand how PCE affects cognition, and the goal of this proposal is to dissect the
molecular mechanisms of memory and synaptic plasticity deficits associated with PCE. Our preliminary data
demonstrate hippocampal-dependent memory impairments in PCE animals are concomitant with synaptic
deficits in the form of decreased long-term potentiation (LTP) and enhanced long-term depression (LTD).
Furthermore, we have demonstrated reductions in polysialylated-NCAM (PSA-NCAM), which is required for
neurogenesis, neuronal pathfinding, and learning and memory. We have previously established that decreased
PSA-NCAM can lead to deficits in LTP by modulating GluN2B-Ras-GRF1-p38 MAPK signaling pathway and
altering the signaling balance of GluN2A- and GluN2B- containing NMDA receptors. Our preliminary data with
PCE also indicates a decrease in GluN2A receptor expression and signaling with no change in GluN2B
expression, indicating an imbalance in signaling. Based on our preliminary and published data, we hypothesize
that PSA-NCAM mediated alterations in GluN2A- and GluN2B- signaling pathways are responsible for the
altered synaptic plasticity and memory deficits resulting from PCE. The objective of this proposal is to dissect
the molecular mechanisms by which PCE induces synaptic plasticity and cognitive deficits. We will use a
multidisciplinary approach including behavioral, electrochemical, electrophysiological, cellular and molecular
methodologies to test our hypotheses. We propose three interrelated but sequentially independent specific
aims: (1) Investigate the molecular mechanisms of behavioral and synaptic plasticity deficits resulting from
PCE, (2) Investigate how PSA-NCAM modifies synaptic transmission and plasticity by regulating NMDA
receptor-mediated signaling in PCE animals, and (3) Determine the functional outcomes of application of a PSA
mimetic & modulation of GluN2A- and GluN2B- containing NMDA receptors on PCE-induced synaptic plasticity
and memory deficits. The data from our study not only points toward a specific mechanism responsible for
PCE-related deficits but will also comprehensively assess the different roles played by synaptic molecules
responsible for plasticity mechanisms closely associated with cognition.

## Key facts

- **NIH application ID:** 10140319
- **Project number:** 5R01DA046723-02
- **Recipient organization:** AUBURN UNIVERSITY AT AUBURN
- **Principal Investigator:** Miranda Nicole Reed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $290,671
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140319

## Citation

> US National Institutes of Health, RePORTER application 10140319, Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies (5R01DA046723-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140319. Licensed CC0.

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