The Antidepressant Fluoxetine Restores Some Lost Neuroplasticity in Old Mice

There is a fair amount of evidence in mice for antidepressants to work via increased plasticity in the brain. This means greater generation and integration of new neurons, and more restructuring of synaptic connections between neurons. In mice, plasticity is lost with age, and here researchers show that a commonly used antidepressant can restore some of that loss. It remains an interesting question as to how much of this mouse research does in fact translate to humans; of late the data regarding plasticity of the human brain has been mixed, suggesting that there may be significant differences between humans and mice in this matter.

In the study the researchers focused on the aging of inhibitory interneurons which is less well understood than that of excitatory neurons, but potentially more crucial to plasticity. The team counted and chronically tracked the structure of inhibitory interneurons in dozens of mice aged to 3, 6, 9, 12 and 18 months (mice are mature by 3 months, live for about 2 years, and 18-month-old mice are already considered quite old). Previous work has shown that inhibitory interneurons retain the ability to dynamically remodel into adulthood. But the team now shows that new growth and plasticity reaches a limit and progressively declines starting at about 6 months. The study also shows that as mice age there is no significant change in the number or variety of inhibitory cells in the brain.

While the decline of dynamic remodeling and plasticity appeared to be natural consequences of aging, they were not immutable, the researchers showed. Prior work had shown that fluoxetine promotes interneuron branch remodeling in young mice, so they decided to see whether it could do so for older mice and restore plasticity as well.

To test this, researchers put the drug in the drinking water of mice at various ages for various amounts of time. Three-month-old mice treated for three months showed little change in dendrite growth compared to untreated controls, but 25 percent of cells in six-month-old mice treated for three months showed significant new growth (at the age of 9 months). But among 3-month-old mice treated for six months, 67 percent of cells showed new growth by the age of 9 months, showing that treatment starting early and lasting for six months had the strongest effect.

"Our finding that fluoxetine treatment in aging mice can attenuate the concurrent age-related declines in interneuron structural and visual cortex functional plasticity suggests it could provide an important therapeutic approach towards mitigation of sensory and cognitive deficits associated with aging, provided it is initiated before severe network deterioration."



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