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Molecular Mechanism of Hippocampal network excitability in a novel, in vivo model of Tuberous Sclerosis Complex

Award Number: R01NS105005
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Overview: The project focuses on understanding the molecular basis of how disrupted calcium homeostasis leads to disrupted hippocampal network activity that results in maladaptive responses in neurons with TSC deficient signaling. Approximately 33% of children who have autism spectrum disorder (ASD) also have epilepsy. Early childhood seizures can result in compromised synaptic plasticity and cognitive impairment, suggesting that the hippocampus may be vulnerable to changes in network excitability. Despite the importance of this problem, the connection between seizure activity and development of ASD is poorly understood. Mammalian Target of rapamycin (mTOR) is a kinase that regulates protein synthesis and is overactive in many complex brain disorders. In the proposed studies, we focus on a mouse model of ASD, Tuberous Sclerosis Complex (TSC), which is a disorder that results from mutations in either the tsc1 or 2 genes. We propose that deficient TSC signaling leads to overactive mTOR and deficient protein synthesis that manifests as epilepsy and ASD. There is no cure for TSC, treatments are limited, and new therapeutic targets are needed. Our previous work has demonstrated that mTOR activity represses the expression of epilepsy-linked ion channels. The proposed studies extend our work to address the molecular mechanisms underlying hippocampal network hyperexcitability in TSC. We will take a multidisciplinary approach to critically test the prediction that reduced expression of the voltage-gated calcium channel subunit a2¿2 by overactive mTOR signaling in TSC leads to dysregulated calcium homeostasis and aberrant hippocampal network activity. (1) At the molecular level, we ask how a2¿2 expression is regulated by mTOR; (2) at the cellular level, we ask what is a2¿2’s role in dendritic calcium signaling and glutamate receptor recycling in TSC deficient dendrites; and (3) at the network level, we address the effect of a2¿2 in promoting aberrant hippocampal network activity. The proposed work is the first to bridge the gap between underlying molecular/cellular mechanisms and hippocampal network hyperexcitability in TSC, using a novel preclinical model to measure spike and seizure threshold for the first time. The strength of our approach allows us to also test several interventions using our novel optogenetic preclinical model of network activity. Notably, seizure medications do not target only the region of the brain that seizures originate, but can reduce hyperexcitable neurons in other parts of the brain, such as the hippocampus where ASD is tightly linked. Thus, we hypothesize that the hippocampus is vulnerable in children with TSC due to neuronal and network hyperexcitabillity. These studies form the foundation for promising new therapeutic strategies for TSC and other mTOR-related, complex brain disorders, with possible clinical applications.


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: 2023 ( Subtotal = $0 )
2023	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	5	9/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $335,999 )
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	5	6/22/2022	NON-COMPETING CONTINUATION	$335,999
														Subtotal = $335,999

Issue Date FY: 2021 ( Subtotal = $424,122 )
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	4	7/6/2021	NON-COMPETING CONTINUATION	$335,999
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	4	7/7/2021	SUPPLEMENT FOR EXPANSION	$88,123
														Subtotal = $424,122

Issue Date FY: 2020 ( Subtotal = $424,122 )
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/19/2020	SUPPLEMENT FOR EXPANSION	$1,003
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/1/2020	SUPPLEMENT FOR EXPANSION	$87,120
2020	2020	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/10/2020	NON-COMPETING CONTINUATION	$335,999
														Subtotal = $424,122

Issue Date FY: 2019 ( Subtotal = $335,999 )
2019	2019	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	7/2/2019	NON-COMPETING CONTINUATION	$335,999
														Subtotal = $335,999

Issue Date FY: 2018 ( Subtotal = $335,999 )
2018	2018	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	7/10/2018	NEW	$335,999
														Subtotal = $335,999

Grand Total All Awards = $1,856,241

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Molecular Mechanism of Hippocampal network excitability in a novel, in vivo model of Tuberous Sclerosis Complex

Award Number: R01NS105005

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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