Reelin Rescues Behavioral, Electrophysiological, and Molecular Metrics of a Chronic Stress Phenotype in a Similar Manner to Ketamine.
Jenessa N Johnston, Josh Allen, Irene Shkolnikov, Carla L Sánchez-Lafuente, Brady S Reive, Kaylene K A Scheil, Stanley Liang, Brian R Christie, Lisa E Kalynchuk, Hector J Caruncho
eNeuro August 2023 DOI: 10.1523/eneuro.0106-23.2023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Exploratory preclinical study Peer reviewed |
|---|---|
| Population | Male Long-Evans rats |
| Interventions | Reelin Ketamine |
| Dose | Reelin 3 µg, i.v.; ketamine 10 mg/kg, i.p. |
| Duration | 21-day chronic corticosterone paradigm; testing 24 hours after acute administration |
| Measures | Forced swim test, sucrose preference test (SPT), in vivo electrophysiology (long-term potentiation), immunohistochemistry, Western blotting |
| Topics | Depression Ketamine Neuroplasticity Esketamine |
| Keywords | Corticosterone Long-term potentiation Reelin |
| Key points | Both acute reelin and ketamine rescued stress-induced behavioral changes and increased hippocampal long-term potentiation in chronically stressed rats, with reelin alone rescuing latency to immobility. Reelin immunoreactivity in the dentate gyrus paralleled these effects, but no significant synaptic-level protein changes were observed. The authors propose that reelin may have rapid-acting antidepressant properties. |
Abstract
Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress. However, research has not yet demonstrated the changes that occur rapidly after peripheral reelin administration. To address this key gap in knowledge, male Long-Evans rats underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 d). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, i.p.), reelin (3 µg, i.v.), or vehicle. Twenty-four hours after administration, rats underwent behavioral or in vivo electrophysiological testing before killing. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was microdissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting. Chronic corticosterone induced a chronic stress phenotype in the forced swim test and sucrose preference test (SPT). Both reelin and ketamine rescued immobility and swimming, however reelin alone rescued latency to immobility. In vivo electrophysiology revealed decreases in hippocampal long-term potentiation (LTP) after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioral and electrophysiological findings, but no significant changes were observed in synaptic-level protein expression. This exploratory research supports the putative rapid-acting antidepressant effects of an acute dose of reelin across behavioral, electrophysiological, and molecular measures.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.