Scientists in the United States have shown that manipulating a novel target in the brain using gene therapy could lead to new treatments for depression.
If replicated in humans, it could open the way for new therapies for millions of patients who don’t respond to existing treatments for depression.
“Drugs currently available for treating depression help most patients, but they stop working for some patients and don’t work from the get-go for others,” said senior author Dr Dane Chetkovich. “There is a real need for new therapies to help patients desperate for alternatives to the available therapeutic options.”
Most existing antidepressants affect mood and emotions by increasing levels of neurotransmitters called monoamines, namely serotonin, dopamine and norepinephrine. But the fact these drugs are not effective for many patients suggests there are additional mechanisms underlying depression yet to be uncovered.
Targeting a region of the brain
In previous research, Chetkovich’s lab and others showed those mechanisms might involve the hippocampus, a region of the brain important for learning, memory and emotional regulation. There they saw changes to HCN channels, typically involved in controlling the electrical activity of cells in the heart and brain, also played a critical role in behaviours linked to depression.
In the new study, they took steps to translate that insight into a potential gene therapy using mouse models. The scientists surgically injected mice with a nontoxic virus engineered to express a gene that turns off HCN channel function in hippocampus neurons.
“When the HCN channels stopped working, the mice behaved as if they’d been given antidepressant medications,” Chetkovich explained.
In contrast, increasing the function of HCN channels removed the antidepressant effect.
To measure depression-like behaviour, the scientists measured how long mice would seek to escape an environment before giving up — a test commonly used by the pharmaceutical industry to screen compounds for effectiveness as antidepressants, including medications currently on the market.
“This work not only identifies a totally new treatment target for depression, it provides a detailed molecular description of the structures that need to be manipulated for it to act as an antidepressant and develops viral tools to do so,” said Chetkovich.