| First Author | Wei X | Year | 2024 |
| Journal | Proc Natl Acad Sci U S A | Volume | 121 |
| Issue | 33 | Pages | e2400420121 |
| PubMed ID | 39106304 | Mgi Jnum | J:353874 |
| Mgi Id | MGI:7714511 | Doi | 10.1073/pnas.2400420121 |
| Citation | Wei X, et al. (2024) A therapeutic small molecule enhances gamma-oscillations and improves cognition/memory in Alzheimer's disease model mice. Proc Natl Acad Sci U S A 121(33):e2400420121 |
| abstractText | Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The gamma-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 gamma-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 gamma-aminobutyric acid type A receptors most likely assembled from alpha1beta2delta 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 gamma-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 gamma-oscillations through enhancing the function of PV+INs. |
