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Determining mechanisms underlying hippocampal network disruption in early amyloid pathology: the role of PV basket cells on sharp wave ripples

Award Number: F31AG062030
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease, characterized by learning and memory deficits and the pathological accumulation of amyloid beta (Aß) protein. Accounting for 60-70% of cases of dementia, the disease has a rapidly expected increase in prevalence and cost to public health as world-wide life expectancy increases. The cause of memory dysfunction in the disease is poorly understood however, particularly at an early time-point of amyloid accumulation. In mouse models of AD, at ages preceding neuronal or synaptic loss, there have been observed alterations in hippocampal sharp wave ripples (SWRs), neuronal population events with a critical role in memory consolidation. The mechanisms underlying this disruption are relatively unexplored however, a critical gap that the research proposed in this fellowship will examine. While it is well-appreciated that amyloid accumulation impairs the synaptic function of excitatory pyramidal cells (PCs), there is growing evidence that inhibitory GABAergic cells are also compromised. Amyloid accumulation has been shown to disrupt the activity of parvalbumin (PV) expressing inhibitory basket cells (PVBCs), cells which have a critical role in regulating SWR events. PV cells are unique in that they are the major neuronal subtype ensheathed in peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that regulate and support cellular activity. This proposal will explore if a preferential amyloid-induced disruption to PVBCs and the PNNs that surround them can account for alterations to SWR events. Parallel biochemical and electrophysiological studies will seek to determine if reduced excitatory input to this cell type results in decreased inhibitory drive to the hippocampal network, potentially causing the hyperexcitable activity often observed in early amyloid pathology. This mechanism will be further explored by monitoring the activity of excitatory PCs, both through patch clamp electrophysiology and calcium imaging to record ensemble dynamics. A biophysical computational model will determine if the proposed PVBC-PC mechanism is sufficient to explain observed SWR and ensemble disruption. The training proposed in the advanced techniques of whole-cell biocytin-injection and computational modeling will facilitate the determination of the neuronal mechanisms underlying hippocampal network disruption in early amyloid pathology. As this activity is critical for memory consolidation, these findings will provide a therapeutic target to potentially ameliorate memory decline.


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: 2023 ( Subtotal = -$7,355 )
2023	2020	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	2	10/17/2022	NON-COMPETING CONTINUATION	-$7,355
														Subtotal = -$7,355

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	002	2	9/29/2022	NON-COMPETING CONTINUATION	$7,437
2022	2020	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	001	2	4/22/2022	NON-COMPETING CONTINUATION	-$7,437
2022	2019	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	1	4/22/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$10,550 )
2021	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	2	5/13/2021	NON-COMPETING CONTINUATION	-$10,550
														Subtotal = -$10,550

Issue Date FY: 2020 ( Subtotal = $32,820 )
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	2	4/22/2020	NON-COMPETING CONTINUATION	$32,820
														Subtotal = $32,820

Issue Date FY: 2019 ( Subtotal = $32,316 )
2019	2019	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	001	1	4/18/2019	NEW	$0
2019	2019	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Aging Research	000	1	4/18/2019	NEW	$32,316
														Subtotal = $32,316

Grand Total All Awards = $47,231

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Determining mechanisms underlying hippocampal network disruption in early amyloid pathology: the role of PV basket cells on sharp wave ripples

Award Number: F31AG062030

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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