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Hippocampal astrocytic Kir4.1 channel function in Type 2 diabetic mice: impact on neuronal hyperexcitability

Award Number: SC2NS124907
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Hippocampal astrocytic Kir4.1 channel function in Type 2 diabetic mice: impact on neuronal hyperexcitability - Epilepsy is one of the most common neurological disorders in the US. Diabetics are a subgroup of patients that are at increased risk of suffering from this condition, increasing their morbidity and mortality. Whereas, 9.3% of the United States population has diabetes. It has been shown that uncontrolled hyperglycemia (diabetes) increases the susceptibility to epileptiform-like activity in the brain but the mechanism is still unknown. There is a critical need in the identification a potential mechanism that may help link diabetes and seizures. Epilepsy is caused by a disruption of neuronal communication. One of the factors that may contribute to epileptiform activity is the accumulation of extracellular potassium [K+]o in active synaptic areas. Astrocytes provide support, deliver nutrients to neuronal circuits and maintain extracellular ion balance. Furthermore, they are one of the most abundant cell types in the brain and they have been highlighted in epilepsy mostly due to decreased capabilities in potassium uptake. One important well-characterized process that relates to epilepsy is the regulation of [K+]o. The Kir4.1 inwardly rectifying potassium channel (Kir4.1) located in astrocytes surrounding synapses largely carries out the process of potassium uptake. The rationale for the proposed study is based on our published data which shows that astrocytes from hippocampal brain slice from diabetic male mice display Kir4.1 channel protein downregulation and significant decrease in potassium uptake capability. The objective of this project is to find a relationship between Kir4.1 downregulation and seizure-like events in the brain of diabetic male and female mice considering sex as a biological variable. Therefore, our Central Hypothesis is that one of the major causes of the epileptic phenotype in diabetic patients is the inability to buffer excess [K+]o by astrocytes due to downregulation of the Kir4.1 channel protein. We will address this by measure astrocytic Kir4.1 channel mRNA and protein levels, test Kir4.1 channel activity in hippocampal astrocytes and assess the epileptiform activity in hippocampal pyramidal neurons in response to 4-aminopyridine application using electrophysiology in female mice. Finally, we will characterize and determine if reinstatement of Kir4.1 channels protein in hippocampal astrocytes via viral delivery will restore astrocytic Kir channel expression, membrane potential, barium sensitive currents and K+ and further correlate this with neuronal epileptiform-like activity in diabetic mice. These results will contribute to new information specifically to the knowledge of diabetes (high glucose) in the brain which may negatively contribute to neurological problems such as the neuronal hyperexcitability seen in epilepsy. Our main goal is to understand how hyperglycemia affects astrocytic homeostatic functions leading to neuronal hyperexcitability.


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: 2026 ( Subtotal = $0 )
2026	2023	UNIVERSIDAD DE PUERTO RICO EN AGUADILLA	C BELT 752, BASE RAMEY	AGUADILLA	PR	00605	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $182,442 )
2023	2023	UNIVERSITY OF PUERTO RICO	252 CALLE BELT	AGUADILLA	PR	00603	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/16/2023	NON-COMPETING CONTINUATION	$115,229
2023	2023	UNIVERSITY OF PUERTO RICO	252 CALLE BELT	AGUADILLA	PR	00603	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/7/2023	SUPPLEMENT FOR EXPANSION	$67,213
														Subtotal = $182,442

Issue Date FY: 2022 ( Subtotal = $198,863 )
2022	2022	UNIVERSITY OF PUERTO RICO	252 BELT ST	AGUADILLA	PR	00604	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/30/2022	SUPPLEMENT FOR EXPANSION	$7,110
2022	2022	UNIVERSITY OF PUERTO RICO	252 BELT ST	AGUADILLA	PR	00604	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/3/2022	NON-COMPETING CONTINUATION	$117,429
2022	2022	UNIVERSITY OF PUERTO RICO	252 BELT ST	AGUADILLA	PR	00604	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	8/4/2022	SUPPLEMENT FOR EXPANSION	$74,324
														Subtotal = $198,863

Issue Date FY: 2021 ( Subtotal = $118,329 )
2021	2021	UNIVERSITY OF PUERTO RICO	252 BELT ST	AGUADILLA	PR	00604	AGUADILLA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/23/2021	NEW	$118,329
														Subtotal = $118,329

Grand Total All Awards = $499,634

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Hippocampal astrocytic Kir4.1 channel function in Type 2 diabetic mice: impact on neuronal hyperexcitability

Award Number: SC2NS124907

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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