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mTOR Hyperactivity Disrupts the Molecular Framework of Inhibitory Synapses

Award Number: F31NS117096
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/04/2021
PERIOD OF PERFORMANCE END DATE: 06/03/2023

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mTOR Hyperactivity Disrupts the Molecular Framework of Inhibitory Synapses - Project Summary Tuberous sclerosis complex (TSC) develops from loss of function mutations in the TSC1 or TSC2 gene, whose protein products associate and inhibit mammalian target of rapamycin complex 1 (mTORC1). In turn, mTOR hyperactivity results, which is considered to be the driving pathological feature of TSC. TSC patients suffer from epilepsy and autism spectrum disorders (ASDs), and TSC researchers hypothesize that seizures in early childhood can cause ASD. Current treatments aim to decrease the likelihood of seizure generation, but these medications have serious side effects. Therefore, it has become increasingly important to identify the molecular mechanism that contributes to seizures and to provide new pharmacological treatments. It is suggested that the imbalance between excitation and inhibition underlies seizures and ASD. Specifically, inhibitory synaptic protein expression is disrupted in these disorders and may be a common hub of dysfunction in ASDs and epilepsy. This study investigates how the inhibitory synapse is dysregulated in TSC. We hypothesize that mTOR hyperactivity in TSC represses the formation of inhibitory synapses through mTORC1-dependent mRNA repression. Utilizing an unbiased bioinformatics approach, we identified a putative mTOR-sensitive inhibitory synaptic protein, vesicular GABA transporter (vGAT)- a presynaptic protein which packages GABA and glycine (inhibitory neurotransmitters) into synaptic vesicles. We will determine if elevated levels of an RNA-binding protein, DJ-1, binds and represses vGAT mRNA translation in vivo in the cortex of TSC1 wildtype compared to TSC1 heterozygous mice. Additionally, with a de novo protein synthesis assay, we will test the hypothesis that mTORC1 represses mRNA translation of vGAT; we will determine if rapamycin treatment (mTORC1 inhibition) and DJ-1 knockdown increase protein synthesis of vGAT in Aim 1. Finally, in Aim 2, we will utilize two complimentary approaches: in vitro electrophysiology and a novel in vitro synapse measuring assay to determine if the number of vGAT-gephyrin synapses are decreased in a TSC1 gene dosage dependent loss, and if mTORC1 inhibition rescues this deficit. Collectively, these two related yet independent aims will help elucidate our mechanistic understanding of how protein synthesis deficits impair the formation of inhibitory synapses.


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: 2024 ( Subtotal = -$4,115 )
2024	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/24/2024	NON-COMPETING CONTINUATION	-$4,115
														Subtotal = -$4,115

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/23/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/13/2022	NON-COMPETING CONTINUATION	$46,753
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/23/2021	NEW	$0
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/23/2021	NEW	$46,036
														Subtotal = $46,036

Grand Total All Awards = $88,673

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mTOR Hyperactivity Disrupts the Molecular Framework of Inhibitory Synapses

Award Number: F31NS117096

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/04/2021

PERIOD OF PERFORMANCE END DATE: 06/03/2023

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