Attentional deficits diminish the quality of life for Alzheimer's disease (AD) patients, however the neural basis for this early impairment is not understood. In mouse models of AD, excitatory neurons are hyperactive near amyloid deposits, which could contribute to defects in information processing underlying behavioral dysfunctions. We hypothesize that hypofunction of cortical GABAergic circuits near amyloid deposits is associated with the aberrant network activity and attentional deficits. To test this hypothesis, we will measure the electrophysiological properties of the major subtypes of GABAergic neurons in an AD mouse model. We will also characterize the dendritic morphologies of the inhibitory interneurons in an AD mouse model and in post-mortem cortical tissue from AD patients. To test the prediction that cholinergic signaling in GABAergic interneurons is compromised, we will measure the ability of acetylcholine to modulate cortical network activity. We will also investigate whether knocking down nicotinic acetylcholine receptors in specific subtypes of GABAergic interneurons can recapitulate the neuropathology. Finally, we will investigate the behavioral relevance by determining whether activating specific GABAergic neuronal populations in the neocortex can alleviate attentional deficits in an AD mouse model. These experiments leverage a combination of optical, electrophysiological, molecular, and behavioral approaches to tease apart the circuit level neuropathology in an AD mouse model. The results will position GABAergic neurotransmission as a point of integration for the synaptic Abeta and cholinergic theories of AD. A positive outcome will also provide evidence for targeting specific cell types for treating attentional deficits in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG047270-05
Application #
9728833
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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