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Deconstructing epileptic circuits in a mouse model of SLC6A1 syndrome

Award Number: F32NS127998
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Deconstructing epileptic circuits in a mouse model of SLC6A1 syndrome - PROJECT SUMMARY & ABSTRACT The SLC6A1 gene has been recently implicated in a spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual and motor disability, collectively named SLC6A1 syndrome. SLC6A1 encodes the GABA transporter GAT1, but the cellular and circuit mechanisms by which SLC6A1 mutations cause SLC6A1 syndrome remain unknown, thus hampering the development of effective treatments. To fill this gap, I propose to dissect the mechanisms that cause epilepsy in a new mouse model carrying a human SLC6A1 mutation. My preliminary data show that Slc6a1 S295L/+ mutation leads to state-dependent seizures in thalamocortical circuits, disrupting sleep. Motivated by these findings, I will test the central hypothesis that thalamic circuits are key regulators of epileptic seizures associated with SLC6A1 syndrome. To test this hypothesis, I will determine the impact of S295L mutation on synaptic and intrinsic properties of thalamocortical neurons and thalamic circuit excitability in brain slices, and on thalamocortical function in vivo. I will also investigate whether thalamic targeting with optogenetic tools can treat epileptic seizures. The proposed work will harness in vitro and in vivo electrophysiological and optogenetic circuit dissection techniques. These results will elucidate our basic understanding of GAT1 dysfunction and assess how the subsequent increased tonic GABA current might impact the thalamocortical circuit in SLC6A1 syndrome. Ultimately, this work will help identify potential therapeutic targets to treat SLC6A1-related epilepsy.


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 = -$6,096 )
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/24/2025	NON-COMPETING CONTINUATION	-$6,096
														Subtotal = -$6,096

Issue Date FY: 2024 ( Subtotal = $36,647 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/12/2024	NON-COMPETING CONTINUATION	$70,052
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/8/2024	NON-COMPETING CONTINUATION	$6,704
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/9/2024	NON-COMPETING CONTINUATION	-$40,109
														Subtotal = $36,647

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/3/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/3/2022	NEW	$67,582
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/3/2022	NEW	$0
														Subtotal = $67,582

Grand Total All Awards = $98,133

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Deconstructing epileptic circuits in a mouse model of SLC6A1 syndrome

Award Number: F32NS127998

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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