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Dynamic GABA and Glutamate Neurotransmission in Alzheimer’s Disease and Aging

Award Number: R01AG070952
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Dynamic GABA and Glutamate Neurotransmission in Alzheimer’s Disease and Aging - PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) progression and normal aging are complex and often heterogeneous processes involving functional changes to neuronal and glial elements that are not just related to neuronal cell loss [1-4, 143]. Prior in vitro and in vivo data support that aberrant regulation of glutamate neuronal systems can be a contributor to neuronal degeneration in aging and likely a contributor to the age-dependent development of AD [1, 4, 6-8]. We think that because there is a dearth of treatment and monitoring options our study will help in the future development of therapeutics and non-invasive spectroscopic monitoring techniques for AD. Recently, we have successfully adapted our enzyme-based microelectrode arrays (MEAs), which are designed to precisely measure tonic and phasic neurotransmitter release in discrete brain structures in awake animals, for use in aged rodents and AD mouse models [54-56, 79, 112]. A major knowledge gap in AD and aging involves changes in the excitatory/inhibitory balance between glutamate (Glu) and GABA release and regulation [9-15]. We believe that the use of our new recording technology will improve our understanding of the glutamate/GABA interplay in an AD model and in normal aging. Our recent studies using this superior technology now allows the measurements of tonic and phasic glutamate levels found that rats >18 months of age have normal or elevated basal Glu levels compared to younger rats. Thus, some animals have elevated glutamate while others do not. As outlined in NIH Notice NOT-AG-18-051 & related announcement PAR-19-070, issues surrounding age and its role in dementia are critical in furthering our understanding of the metabolic and pathological changes that affect signaling in neuronal circuits and networks. We will use young and aged normal and the APPNLh/NLh x PS1P264L/P264L knock-in mouse (APP/PS1 KI) that does not overexpress APP or PS1, or use artificial promoters, making it an ideal system for the study of how aging affects the development of AD-related neuropathology [86- 90]. We will use our novel methods to simultaneously record GABA and glutamate signaling in either the CA1 region of the hippocampus or Frontal Cortex. We will first behaviorally characterize all animals so that we can determine potential correlations between the behavioral performance of mice and glutamate and GABA release and/or regulation in the hippocampus (Morris water maze test) and frontal cortex (spatial memory variant of Morris water maze test) [115] and performed as per [116]. Finally, mice that are studied will undergo a pathological examination to evaluate neurodegeneration by evaluating reactive gliosis may be present by looking at Iba1 and GFAP. Collectively, these studies will allow us to compare the effects of normal aging in male and female to the effects seen from a mouse model of AD on the balance of glutamate and GABA signaling and its relationship(s) to cognitive function in both male and female animals towards the development of novel therapeutics to possibly treat the development and progression of AD.


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 = $649,861 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	3/4/2025	NON-COMPETING CONTINUATION	$596,811
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	3	6/13/2025	NON-COMPETING CONTINUATION	$53,050
														Subtotal = $649,861

Issue Date FY: 2024 ( Subtotal = $1,389,385 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	2	7/11/2024	EXTENSION WITH OR WITHOUT FUNDS	$66,313
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	002	2	8/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$726,262
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	2	1/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$596,810
														Subtotal = $1,389,385

Grand Total All Awards = $2,039,246

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Dynamic GABA and Glutamate Neurotransmission in Alzheimer’s Disease and Aging

Award Number: R01AG070952

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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