July 2, 2012 | 2
When I saw all the headlines going around focused on this paper, I KNEW I had to check it out. Heck, sometimes Twitter is faster than my Pubmed alerts! “Chronic Stress, Mood Disorders Linked In New Research On Rats“, “Stress Blocks Gene That Guards Brain Against Depression”
The link between stress, dysregulations of the hypothalamic pituitary adrenal axis, and depressive-like symptoms in animals and depression in humans is actually really well known. We can put down our “stress linked to depression” headlines, now. In fact, other papers from the same lab as this paper have shown the link between stress and depression many, many times. We know stress correlates with depression and that stress can produce depressive like symptoms in animals.
But this paper? This paper is very new, and very cool! Not because it shows a link between stress and depression. This new finding, the gene neuritin, joins a group of things linking stress and depression, including BDNF, glucocorticoid receptors, serotonin 1A receptors, and many more. This is not the first link between stress and depression and it won’t be the last. But it IS a cool finding. Because it presents us with a new antidepressant target, and we can always use one of those.
Son et al. “Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress” PNAS, 2012.
All of the clinical antidepressants that are currently on the market work through one specific mechanism: they increase the levels of certain neurotransmitters in your brain. Increasing levels of serotonin or norepinephrine over a long period of time can alleviate symptoms of depression. Of course, the drugs have slight tweaks in HOW they elevate serotonin or norepinephrine. Some inhibit the recycling of these chemicals (the SSRIs and the SNRIs), some inhibit their breakdown, but either one increases the concentration of neurotransmitter in the spaces between your neurons. Long term administration of these drugs can help alleviate depression.
But it doesn’t help in all people. Only about 1/3 of patients get relief of their symptoms from the first drug they try, and only about 2/3 of patients will be successfully treated even after trying multiple drugs. Of those, many people only get mild relief from their symptoms. These are not good numbers. So scientists have been looking for new drug targets, in the hopes of creating new drugs that could be more effective in more patients.
Here’s where we get to mechanism. We’re still not sure how antidepressants have their effects (when they work). We know that just increasing serotonin levels does not relieve depression, and that low levels of serotonin or norepinephrine alone can’t explain all the clinical symptoms. So other theories of what causes depression have come up, some of them related to serotonin and norepinephrine, but which are usually a bit more complex. One of them has to do with neuron birth and growth, what we call neurogenesis (birth), and with neuronal plasticity, which is how neurons change, strengthen, or lose the connections between each other. This is particularly important in the hippocampus, an area of the brain that people usually think of as being important to learning and memory, but which is also extremely important in mood disorders like depression.
And this is where neuritin comes in. Neuritin is a protein from a gene that is involved in neuronal plasticity, helping neurons mature and dendrites grow. People (and animal models) with major depressive disorder (or depressive-like symptoms in animals) often show problems with the hippocampus, with decreased hippocampal size and decreased neurogenesis, as well as decreases in dendritic arborization (which refers to how the dendrites of a neuron spread out as they grow to connect to other neurons, and if arborization sounds tree-ish, that’s because it’s supposed to, that’s a lot what it looks like). So the authors of this study wanted to look at neuritin, to see if this particular cadidate related to neuronal maturation and dendrite growth could be a mediator in depression.
And this is where stress comes in. We know that if we stress a mouse, for example, you’ll get major decreases in neurogenesis, behavioral changes that are considered “depressive-like”, and decreases in dendrite arborization. Could neuritin play a role in this? And if it does, what does it mean?
To look at this, the authors of this study used chronic unpredictable stress in rats. This involves making sure the rats are chronically stressed, giving them things like loud music, lights on at night, uncomfortable temperatures, or wet bedding in a rnadom, continuous rotation that changes several times per day (the constant switches are sometimes thought to be just as stressful to the researchers as they are to the rats!). After the rats had been on this paradigm for a while, the authors gave some of them treatment with fluoxetine (Prozac, an SSRI antidepressant) and looked at their neuritin expression in the hippocampus.
You can see above that the animals treated with chronic stress (the red bars) showed decreased neuritin in all areas of the hippocampus compared to control (grey bars). Treatment with fluoxetine (blue bars) reversed this decrease, and fluoxetine alone (green bars) also increased neuritin expression (I kind of loathe the color scheme, but you can’t deny those bars make it easy to tell what’s what!).
You can also see here that neuritin had dramatic effects on the dentrites in the rats’ brains. Animals given neuritin had increases in synaptic density compared to controls.
So now we know that neuritin can increase dendrite growth, and that it increases with antidepressant treatment and decreases with stress. But can it PREVENT the effects of stress? To find this out, the authors used a viral vector which contained neuritin DNA, putting it in to the rats’ brains to increase neuritin expression.
And those rats with increased neuritin expression did not show the decreases in sucrose preference that come with chronic stress (the green bars), and didn’t show the decreased dendritic spine density that goes with chronic stress either (also the green bars). Neuritin prevented the effects of stress in these animals. Not only that, when they used another viral vector to knock DOWN neuritin, the animals displayed more depressive like behaviors in the forced swim test.
And neuritin even increased hippocampal dependent memory (the red and green bars), which is another important aspect of dendritic arborization in the hippocampus.
So it looks like neuritin might be a new and important target in studies of depression. While this doesn’t mean that, say, decreased neuritin causes depression (we don’t have any proof of that in humans), it does mean that increasing neuritin by some mechanism might be able to boost antidepressant efficacy, or possibly even make a new antidepressant, though many, many more studies would be needed before that happens. For example, we don’t currently have drugs to increase neuritin that work in animals or humans. And while neuritin itself (say, through mutations or epigenetic changes) could also play a role in depressive symptoms in humans, we don’t know that yet. But neuritin represents an interesting new player in the game of stress and depression, and potentially an interesting new target for studies in humans and animals, and eventually, maybe for new and better antidepressants.
Son H, Banasr M, Choi M, Chae SY, Licznerski P, Lee B, Voleti B, Li N, Lepack A, Fournier NM, Lee KR, Lee IY, Kim J, Kim JH, Kim YH, Jung SJ, & Duman RS (2012). Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. Proceedings of the National Academy of Sciences of the United States of America PMID: 22733766