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Understanding the temporal regulation of inhibitory synapse depression and elimination in the context of cerebral ischemia

Award Number: F99NS120640
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Understanding the temporal regulation of inhibitory synapse depression and elimination in the context of cerebral ischemia - PROJECT SUMMARY/ABSTRACT Inhibitory synapses are crucial for maintaining correct neuronal excitability, which is important for efficient circuitry and proper brain function. Shifts in neuronal excitability have been implicated in a variety of neurological disorders, including ischemia. Based on cell-type specific vulnerabilities, the oxygen and glucose deprivation (OGD) observed in various brain regions including the hippocampus leads to differential effects that may alter neuronal long-term function. The hippocampus is particularly a vulnerable brain region that experiences either delayed cell-death in the CA1 region or resistance to delayed-cell death and shifts in long-term excitability in the CA3 region. Cell-type specific synaptic alterations to neuronal populations may contribute to these ischemic-induced changes. Even though alterations at excitatory synapses are well defined, our knowledge of alterations at the inhibitory synapse remain elusive. Inhibitory GABAA receptors (GABAARs) mediate the majority of fast synaptic inhibition in the brain. The number of postsynaptic GABAARs influences inhibitory strength; therefore, GABAAR trafficking to and from synaptic sites or the neuronal surface is an important regulator of overall inhibitory synaptic strength. During OGD, GABAARs are downregulated from the neuronal surface in hippocampal neurons. Moreover, GABAAR phosphorylation status influences the synaptic declustering or removal of receptors from the neuronal surface during OGD in hippocampal neurons. However, mechanisms that regulate these differences in either synaptic clustering or surface GABAAR expression following an ischemic insult in brain regions with varying susceptibilities remain undefined. In this project, I propose that GABAAR declustering and endocytosis mechanisms are differentially regulated in distinct neuronal populations during OGD to influence GABAAR downregulation based on region-specific vulnerability. Moreover, I hypothesize that these cell-type specific mechanisms drive increased neuronal excitability during OGD due to increase synaptic declustering and decreased surface expression of GABAARs in vulnerable neuronal populations. Based on this, I plan to investigate (i) mechanisms of synaptic GABAAR declustering and surface downregulation in hippocampal pyramidal neurons following OGD (ii) probe the temporal regulation to determine the sequential flow of events promoting GABAAR loss and (iii) use an in vivo model of cerebral ischemia to compare cell-type specific mechanisms in CA1 and CA3 hippocampus that may be differentially regulated based on neuronal susceptibility to OGD. Specifically, I plan to investigate the role of phosphatases in regulating GABAAR phosphorylation state to promote GABAAR declustering and endocytosis during OGD in both vulnerable neuronal populations. The results of this project will establish mechanisms that are specific to GABAAR downregulation in vulnerable populations during OGD, providing novel targets for future therapeutic intervention.


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 = -$946 )
2024	2022	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/31/2023	NON-COMPETING CONTINUATION	-$946
														Subtotal = -$946

Issue Date FY: 2022 ( Subtotal = $36,861 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/24/2022	NON-COMPETING CONTINUATION	$716
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/8/2021	NON-COMPETING CONTINUATION	$36,145
														Subtotal = $36,861

Issue Date FY: 2021 ( Subtotal = $35,629 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/3/2020	NEW	$35,629
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/3/2020	NEW	$0
														Subtotal = $35,629

Grand Total All Awards = $71,544

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Understanding the temporal regulation of inhibitory synapse depression and elimination in the context of cerebral ischemia

Award Number: F99NS120640

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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