Reelin injections could treat stress-related psychiatric conditions

One in eight Canadians will experience major depression at some point in their lives.

Medication is one of the many ways to treat depression, and a new first-author paper from Josh Allen (Caruncho / Kalynchuk Lab) shows Reelin-based drugs could potentially be used in future pharmaceutical therapies for this and other mood disorders.

Reelin is a protein that plays a role both in brain development and, in adults, neural plasticity. Lower levels of Reelin are associated with major depressive disorder, as well as schizophrenia and bipolar disorder.

Josh’s research, which was published in Neuropharmacology, found that administering Reelin via peripheral i.v. injections has antidepressant-like effects in a preclinical model that is relevant for stress-related disorders.

As people with chronic stress have a significantly higher risk of developing depression, the researchers first injected subjects with a stress hormone known as corticosterone (CORT) for several weeks. These CORT injections lowered levels of Reelin in the dentate gyrus subgranular zone of the hippocampus, and induced depressive-like behaviour and neurochemical deficits that are associated with depression.

Josh’s research found that subsequent Reelin injections reversed many of the CORT-induced chemical changes in this area of the brain, such as alterations to the neurotransmitter receptors for glutamate and gamma-aminobutyric acid (GABA), thus having an antidepressant-like effect on the subject.

The team also found that both multiple and single injections of Reelin could produce positive changes. Indeed, a single dose could improve behavioural and neurochemical changes in 24 hours. These fast-acting properties may be due to some of the same molecular mechanisms underlying the antidepressant effect of ketamine. Ketamine is already used as a fast-acting therapy for treatment-resistant depression, though the drug is associated with several risks due to its blockade of the N-methyl-D-aspartate (NMDA) receptor. Reelin, on the other hand, maintains baseline NMDA receptor function.  

However, Josh’s research found that Reelin injections did not solve all of the CORT-induced issues. CORT also slowed down the maturation of adult-born neurons in the hippocampus, but the Reelin injections didn’t seem to have an effect on this deficit, suggesting that the creation of new neurons in this part of the brain does not underlie the antidepressant-like effects of Reelin.

This work was supported by a NSERC Discovery Grant (awarded to PhD supervisors Dr. Hector Caruncho and Dr. Lisa Kalynchuk) and a CIHR-CRC (awarded to Dr. Caruncho).