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Molecular Mechanisms of ADHD in Neurofibromatosis Type 1

Award Number: F30MH122100
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Molecular Mechanisms of ADHD in Neurofibromatosis Type 1 - 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. Unlike the general population, attention deficits affect boys and girls equally in NF1. Few studies have investigated the underlying mechanisms contributing to high incidence of ADHD diagnosis in NF1. Using a murine experimental model system of NF1, mice haploinsufficient for the NF1 gene (Nf1+/-), our preliminary data in male mice show deficits in behavioral inhibition, a key component of ADHD, as exhibited by hyperactivity in open field, increased fall frequency in cliff avoidance reaction task, and increased frequency of small reward choice in delay discounting task, rescuable by ADHD medication (guanfacine 0.3 mg/kg, i.p.) administration. The first aim of this proposed study will elucidate the brain mechanisms underlying deficits in behavioral inhibition, and will be powered to detect male and female differences in behavior and corresponding measures of circuitry activity including in vivo recordings in the prefrontal cortex. In the second aim, we propose a genetic rescue for these observed behavioral inhibition deficits. NF1 is caused by reduced levels of neurofibromin, a RAS GTPase-activating protein, resulting in RAS-MAPK-ERK hyperactivation. Currently, there are no available treatments for cognitive deficits in NF1 that target RAS-MAPK-ERK hyperactivation. This project, proposes a novel mechanism for treatment of cognitive deficits in NF1 by restoring neurofibromin levels through modulation of the ubiquitin-proteasome pathway. Overall, this project will characterize clinically relevant circuits underlying behavioral inhibition deficits, a key feature of ADHD, in males and females. Additionally, this proposal will address the need for a treatment target in NF1 that has the potential to address the many symptoms patients may experience including cognitive deficits, tumors, and neurocutaneous symptoms. Modulation of the neurofibromin ubiquitin- proteasome pathway may provide a novel and safer pharmacologic target for treating NF1.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$7,956 )
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	4	1/23/2025	SUPPLEMENT FOR EXPANSION	-$3,000
2025	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	4	1/23/2025	NON-COMPETING CONTINUATION	-$4,956
														Subtotal = -$7,956

Issue Date FY: 2024 ( Subtotal = $3,000 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	4	1/3/2024	SUPPLEMENT FOR EXPANSION	$2,500
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	4	8/21/2024	SUPPLEMENT FOR EXPANSION	$500
														Subtotal = $3,000

Issue Date FY: 2023 ( Subtotal = $45,908 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	4	8/10/2023	NON-COMPETING CONTINUATION	$45,908
														Subtotal = $45,908

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	3	6/6/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $37,165 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	2	6/11/2021	NON-COMPETING CONTINUATION	$37,165
														Subtotal = $37,165

Issue Date FY: 2020 ( Subtotal = $36,649 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	001	1	5/15/2020	NEW	$0
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Mental Health Research Grants	000	1	5/15/2020	NEW	$36,649
														Subtotal = $36,649

Grand Total All Awards = $166,518

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Molecular Mechanisms of ADHD in Neurofibromatosis Type 1

Award Number: F30MH122100

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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