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Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo

Award Number: R01NS105767
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 In several brain disorders including epilepsy, stroke and traumatic brain injury, an imbalance between the excitatory and inhibitory (E/I) neurotransmitter systems exists. Understanding fully the cellular and molecular processes that underlie normal, physiological transmission is the first step in determining how aberrations of such might be countered to provide such individuals with E/I imbalance symptomatic relief. Recent evidence from our lab demonstrates a role for the cystine/glutamate antiporter System xc- (Sxc-) ─ which exports glutamate and imports cystine, the latter of which is the rate-limiting substrate for the synthesis of the thiol antioxidant glutathione ─ in maintenance of E/I balance. Specifically, we find that sut/sut mice, which harbor a natural mutation in SLC7a11 (SLC7a11sut/sut) and are therefore devoid of Sxc-, are considerably more hyperexcitable than their wild-type littermates upon acute challenge with kainic acid or pentylenetetrazole. Paradoxically, after repeated sub-acute/sub-chronic administration of the same chemoconvulsants, SLC7a11sut/sut mice exhibit signs of hypoexcitability, a response polar opposite to that which occurs in wild-type littermate controls. The idea that these paradoxical findings may result from the same underlying mechanism ─ namely synaptic scaling ─ will be explored in this proposal. State-of-the-art in vivo sensor technology, as well as, cellular, molecular and pharmacological approaches will be used to test the hypothesis that chronic loss of Sxc- leads to a scaling up of glutamate receptors under basal conditions, whereas scaling down occurs under conditions of enhanced neuronal activity ─ both in efforts to stabilize neuronal firing. Whether these finding are mediated by changes in glutamate and/or glutathione will also be explored. Studies to determine the cellular specificity of response, with specific focus on the role of the astrocyte, are also planned. Overall, these studies are designed to increase our mechanistic understanding of the contribution of astrocyte Sxc- to glutamate, glutathione and activity homeostasis in in vivo brain. More broadly, these efforts complement other ongoing efforts to identify targets to treat the E/I imbalance that exists in many neurological disorders.


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 = $0 )
2024	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $350,946 )
2022	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	6/24/2022	NON-COMPETING CONTINUATION	$23,399
2022	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/10/2022	NON-COMPETING CONTINUATION	$327,547
														Subtotal = $350,946

Issue Date FY: 2021 ( Subtotal = $349,091 )
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/22/2021	NON-COMPETING CONTINUATION	$349,091
														Subtotal = $349,091

Issue Date FY: 2020 ( Subtotal = $497,234 )
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/28/2020	NON-COMPETING CONTINUATION	$347,234
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/9/2020	SUPPLEMENT FOR EXPANSION	$150,000
														Subtotal = $497,234

Issue Date FY: 2019 ( Subtotal = $367,159 )
2019	2019	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/15/2019	NON-COMPETING CONTINUATION	$367,159
														Subtotal = $367,159

Issue Date FY: 2018 ( Subtotal = $382,534 )
2018	2018	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/16/2018	SUPPLEMENT FOR EXPANSION	$34,737
2018	2018	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/27/2018	NEW	$347,797
														Subtotal = $382,534

Grand Total All Awards = $1,946,964

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Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo

Award Number: R01NS105767

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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