The popular antidepressant Prozac may work, in part, by turning back the clock on old neurons in the prefrontal cortex—the thinking, cognitive region of the brain—making them “young” again. But some researchers have their reservations about preliminary findings that Fujita Health University systems medical science professor Tsuyoshi Miyakawa reported in a study published in the Nov. 4 issue of Molecular Brain.
It is increasingly being reported that Prozac and other selective serotonin reuptake inhibitors (SSRIs) may work by spurring immature stem cells, in the adult brain, to proliferate and differentiate. But the notion the drugs can make mature neurons dedifferentiate is new, and far more controversial.
“There is no doubt that fluoxetine (Prozac) works on neural stem cells, but it also works on adult neurons for sure,” Miyakawa tells Drug Discovery & Development. “The latter effect is so dramatic. It drastically changes the gene expression pattern and functional properties of adult neurons (at least in the dentate gyrus). Adult neurons greatly outnumber the new neurons generated from neural stem cells in our work. So, we guess that the dematuration effects on adult neurons would have greater functional importance than the effect of the drug on neural stem cells.”
In a 2008 Science paper, a different team offered a similar message, more viscerally. Chronic administration of Prozac caused the visual cortex of adult rats with amblyopia, also known as lazy eye, to revert to an earlier phase of life when retinal neurons are plastic. A patch then placed on the good eye resulted in rewired brains, curing the ambylopia. Patches work on human children with amblyopia, sans Prozac, as their visual cortices are still young and plastic: a kind of natural rewiring. But the patch doesn’t work for human adults as their visual cortices are no longer pliable. Prozac, however, did the job for adult rats.
Previously, Miyakawa and others have found that Prozac may prompt cells to dedifferentiate in the adult brain’s dentate gyrus and amygdala, but few have suspected that this process can occur in the critical cortex as well.
In the recent study, Miyakawa’s group found certain neurons in the mouse prefrontal cortex, subjected to chronic Prozac, also seemed to regain plasticity. There was reduced expression, so apparent dedifferentiation, of some genes marking mature parvalbumin-positive gabaergic neurons, and increased expression of some genes marking immaturity. Neuron number stayed roughly the same.
Schizophrenia is marked in part by similar deficits in those neurons, according to the group. It is possible, the group believes, that dematuration explains some Prozac side effects, such as aggression and violence. “Aggression and violence are associated with deficits in the prefrontal cortex of humans, where activation of gabaergic interneurons decreases,” the group wrote.
“We are confident that some partial dedifferentiation, probably specific to parvalbumin-positive cells, is happening in the prefrontal cortex of fluoxetine-treated mice,” says Miyakawa. The gene expression pattern of the prefrontal cortex treated with fluoxetine, and that of naturally immature parvalbumin-positive cells, are similar to each other. You can see that 25 genes are significantly changed in both conditions, and 23 out of 25 genes are changed in the same directions. That is, six maturation marker genes of parvalbumin-positive cells are downregulated, and 17 immature marker genes are upregulated, in fluoxetine-treated adult prefrontal cortex.”
In past studies his group found that “in the dentate gyrus of the hippocampus, dematuration is more obvious and clear. That is, 246 maturation marker genes are down-regulated and 140 immature marker genes are up-regulated in fluoxetine-treated adult dentate gyrus. The dematuration of parvalbumnin-positive neurons induced by anti-depressants is similar to the findings in the post-mortem brains of the patients with schizophrenia. `Induced-youth’ of the parvalbumin-positive neurons in the prefrontal cortex could be good for a certain type of people with depression—but could cause non-preferable side effects for others.”
Ultimately, the work could help “revolutionize” antidepressive drugs, he says.
But Harvard University neurologist Ole Isacson cautions that the new paper, “describes by non-quantitative measures—histology using antibodies—the presence of some broadly expressed peptides in some interneurons. The speculations made are not based on any real hard evidence. The speculations would possibly mean something, if they had linked their histology with any measures of behavior, function and physiology of the brain in their study. Not so.”
Isacson adds “Prozac and related substances can simply increase or decrease the gene expression of as many as 50 genes or so, within many neurons, many anatomical networks, after a few days of treatment. Consequently, the peptides or proteins that are expressed can be seen by immunohistochemistry—as in the paper. However, one can start with another set of molecules, postulate three totally different proteins than those they studied, and simply (contend) the neurons are adapting after Prozac exposure.”
Any such protein changes “may actually relate to more, or less, release of neurotransmitter in five or six different networks in the brain; networks they did not study. Such neurotransmitter changes could explain functional effects/treatment of symptoms and cell biology just as well as their speculations.” More work, he says, needs to be done.
