Ketamine reverses chronic stress-induced behavioral changes via Ca2+-permeable AMPA receptors in mice
Joshua C. Flowers, Paige E. Vetter, McKennon J. Wiles, Seung Hyun Roh, Ellison R. Black, Evelina Bouckova, Madison H. Wustrau, Rahmi Lee, Sang-Hun Lee, Seonil Kim
bioRxiv Preprint Server October 7, 2024 preprint DOI: 10.1101/2024.10.07.616991
Summary
Chronic stress can profoundly alter brain function, but a new finding offers hope: a compound effectively reverses stress-induced behavioral changes in mice. This positive outcome is linked to its ability to activate specific brain receptors, which enhances neural connections vital for mood and cognition. This mechanism provides a promising understanding of how to counteract the debilitating effects of chronic stress.
Abstract
Background and Purpose Chronic stress affects brain functions leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)-mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low-dose ketamine decreases anxiety-and depression-like behaviors in naïve animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP-AMPARs in the actions of ketamine’s antistress effects is largely unknown.