| Title: |
A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice |
| Authors: |
Wei, Xiaofei; Campagna, Jesus J; Jagodzinska, Barbara; Wi, Dongwook; Cohn, Whitaker; Lee, Jessica T; Zhu, Chunni; Huang, Christine S; Molnár, László; Houser, Carolyn R; John, Varghese; Mody, Istvan |
| Source: |
Proceedings of the National Academy of Sciences of the United States of America, vol 121, iss 33 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 5202 Biological Psychology (for-2020); 3209 Neurosciences (for-2020); 52 Psychology (for-2020); 3214 Pharmacology and Pharmaceutical Sciences (for-2020); Neurosciences (rcdc); Dementia (rcdc); Acquired Cognitive Impairment (rcdc); Behavioral and Social Science (rcdc); Brain Disorders (rcdc); Neurodegenerative (rcdc); Aging (rcdc); Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc); Alzheimer's Disease (rcdc); Mental Health (rcdc); 5.1 Pharmaceuticals (hrcs-rac); Mental health (hrcs-hc); Neurological (hrcs-hc); Animals (mesh); Alzheimer Disease (mesh); Mice (mesh); Disease Models; Animal (mesh); Cognition (mesh); Gamma Rhythm (mesh); Memory (mesh); Receptors; GABA-A (mesh); Mice; Transgenic (mesh) |
| Description: |
Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt2853s836; https://escholarship.org/uc/item/2853s836; https://escholarship.org/content/qt2853s836/qt2853s836.pdf |
| DOI: |
10.1073/pnas.2400420121 |
| Availability: |
https://escholarship.org/uc/item/2853s836; https://escholarship.org/content/qt2853s836/qt2853s836.pdf; https://doi.org/10.1073/pnas.2400420121 |
| Rights: |
CC-BY-NC-ND |
| Accession Number: |
edsbas.A487C66D |
| Database: |
BASE |