# Investigating the neural mechanisms through which NF1 mutation alters vulnerability to an ADHD phenotype

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $412,475

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurofibromatosis type 1 (NF1) is a common inherited genetic disorder with a variety of symptoms, most
commonly as neurocutaneous lesions and developmental disorders, and less commonly with tumors. Cognitive
symptoms such as attentional deficits affect up to 80% of patients, with diagnosis of attention deficit
hyperactivity disorder (ADHD) estimated at 50% in NF1 patients. Few studies have investigated the underlying
mechanisms contributing to high incidence of ADHD diagnosis in NF1. Male mice haploinsufficient for the
neurofibromin gene (Nf1+/-) recapitulate the cognitive deficits evident in patients. Our recent data suggest that
male Nf1+/- mice exhibit hyperactivity in an open field, increased risky behavior in a cliff avoidance test, and
increased impulsivity in a delay discounting task compared to wild-type (WT) males. These behavioral deficits
were all attenuated with systemic treatment with a commonly prescribed, non-stimulant ADHD drug,
guanfacine. Our data suggest that Nf1+/- mice exhibiting ADHD phenotypes rescued by pharmacotherapy used
in NF1 patients not only provides an experimental system for translational research in NF1, but also yields a
novel direction in the ADHD research field by addressing a monogenic cause of ADHD phenotypes.
Dysfunction of the dopamine (DA) and/or norepinephrine neural systems is a commonly proposed mechanism
that leads to ADHD. Dysfunction of these systems is evident in NF1 mouse models, but the mechanism by
which dopamine plays a role in cognitive dysfunction in NF1 is still unclear. Our overall hypothesis is that
abnormal regulation of DA homeostasis in cortical-striatal circuitry due to NF1 mutation contributes to deficits in
behavioral inhibition in Nf1+/- mice. The first aim of the proposed study will elucidate the role of neurofibromin in
cortical and striatal neural regions in behavioral inhibition. We hypothesize that selective deletion of
neurofibromin in the prefrontal cortex (PFC) and/or nucleus accumbens (NAc) will result in behavioral inhibition
deficits. In the second aim, we will determine whether Nf1+/- mice demonstrate alterations in dopamine (DA)
homeostasis within cortical-striatal circuitry. We predict that Nf1+/- mice will display decreased DA as well as
increased D1 receptor mRNA expression in the PFC. Furthermore, we anticipate that Nf1+/- mice will exhibit
decreased D2 receptor levels in the NAc. Finally, we will explore the role of DA receptors in the cognitive deficits
observed in Nf1+/- mice. We hypothesize that selective deletion of Nf1 within D1 receptor-expressing neurons in
the PFC or D2-receptor-expressing neurons in the NAc will result in increased impulsivity similar to that
observed in Nf1+/- mice. Overall, the studies proposed here will identify dysfunctional neuronal circuit(s) and
signaling mechanisms associated with behavioral inhibition in NF1 using a translational experimental system.

## Key facts

- **NIH application ID:** 10110292
- **Project number:** 1R21NS119999-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JODI L LUKKES
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,475
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110292

## Citation

> US National Institutes of Health, RePORTER application 10110292, Investigating the neural mechanisms through which NF1 mutation alters vulnerability to an ADHD phenotype (1R21NS119999-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10110292. Licensed CC0.

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