Reelin rescues behavioral, electrophysiological, and molecular metrics of a chronic stress phenotype in a similar manner to ketamine.

Over the past decade, ketamine, an N -methyl-d-aspartate 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 days). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, intraperitoneally), reelin (3 µg, intravenously), or vehicle. 24 hours after administration, rats underwent behavioural or in vivo electrophysiological testing before sacrifice. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was micro-dissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting.Chronic stress induced a chronic stress phenotype in the forced swim test and sucrose preference test. 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 after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioural 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 behavioural, electrophysiological, and molecular measures. Significance Statement The discovery of ketamine as a rapid-acting antidepressant has been the first major neuropharmacological discovery in decades. However, adverse side effects limit the widespread use of ketamine to certain patient populations. Reelin, a protein that is downregulated in patients with depression, appears to work on similar pathways to the antidepressant effects of ketamine. This study demonstrates that an acute peripheral dose of reelin may rescue certain behavioral, electrophysiological, and molecular deficits in a chronic stress phenotype. The upregulation of reelin expression may provide a novel therapeutic target that could be useful in many patient populations.