Vitamin A, Brain Shrinkage and Depression

It's known that a deficiency or an excess of vitamin A, otherwise known as retinol, and its derivative retinoic acid can affect the birth of new nerve cells, but is this true in adults too?  Chris Smith spoke to Peter McCaffery...

Peter -   Well, that's why we're interested because there's so little known about how vitamin A and retinoic acid actually function in the brain.  There's a huge amount of work done on the developing brain, so it's relatively well understood how these compounds actually control the patterning of gene expression in the embryonic brain.  But it's now beginning to be understood to a greater extent that retinoic acid has important function in the adult brain.

A link with this story is the side effects of a drug called isotretinoin which is a very effective drug used for acne.  There have been, however, despite its effectiveness, some rather controversial claimed side effects, one is headaches.  It literally makes the brain swell.  There's something called pseudotumour cerebri, where excess levels of retinoic acid or even the vitamin itself,  if you have too many carrots, there are some people who've really obsessively taken vitamin A through large amounts of carrot juice and the brain can literally start to swell and pushes on the back of the eye, and that gives the appearance of a tumour.  But the more controversial side effects are things like depression and even suicidal depression.  And the controversy comes there because people using isotretinoin are teenagers, who are more likely to have depression or perhaps even suicidal depression. So is it the drug itself that's inducing depression or is it just coincidence that it's this particular age group that's using it?

Chris -   For that to be the case, it's got to be biochemically plausible.  Is there any way in which the brain could respond to the presence of an augmented level of vitamin A or vitamin A-like agent?

Peter -   Well that's exactly right.  Our work and the studies of others have shown that cells, neurons in the brain, can respond to retinoic acid.

Chris -   Is that because they have a receptor on them, a docking station for the molecule, a bit like, you were saying during embryonic development, cells respond to the presence of the chemical and change the behaviour, adult cells in the nervous system also have receptors that will respond to the presence of the chemical?

Peter -   That's exactly right.  The neurons in the brain express particular receptors that are present in the nucleus and they control the genes that are essential to regulate the cell function.  Now there's two areas that we're particularly interested in regarding the brain where we think it has particularly powerful actions.  On is the hippocampus and that's an area where it's involved in learning and memory, and has links with depression, and the other region that we've become particularly interested in lately is a region called the hypothalamus, and that controls the hormones of the body.

In the hippocampus, we've got very good evidence that it's involved in a process called neurogenesis.  It's been recognised really over the last 10, 15 or so years that new neurons are being born in the hippocampus and there's been a lot of excitement in this particular area, for one reason, new neurons can probably help certain types of memory, but also it has been proposed that a decrease in the number of these new neurons can contribute to depression.  We've shown that too much retinoic acid, at least in the mouse, can actually suppress the number of new neurons being born.  And we've shown that this in fact has a detrimental effect on learning and memory, because that's one of the functions of hippocampus, but we would also propose that it may promote depression because of this inhibition or neurogenesis.

In the hypothalamus, this is the region that controls the hormone levels, we've been studying this, again in animal models, and we've been interested in what's called photoperiodicity and that is the changes in the brain and the body that occur between the seasons.  We're comparing the effects of the short days that occur in winter with long days that occur in the summer.  It's known that there are big changes between those two conditions, and that controls weight gain, energy balance, animals tend to get fatter going into the summer, and leaner into the winter, and the hypothalamus is the brain region that controls that.  So we've found that between those two seasons, retinoic acid changes dramatically itself.  So there's much more, much more powerful retinoic acid signalling during the periods of summer compared to the short days.  So it seems to be an element that regulates the hypothalamus between those two conditions.

Chris -   So if you take a supplement of vitamin A, what is the implication then for the function of your hypothalamus?  How does that impact on physiology?

Peter -   If you don't overdo those supplements, you should be fine because the body has this great set of mechanisms.  If you get too much of something, it really dampens it down and controls it, but if you really go whole hog and you know, take vitamin A supplements and extra carrots and liver, yes, you can push it too far, and the consequences, at least from our studies in animal models, would suggest there would be a disregulation in the hypothalamus.  And this could influence the balance of hormones, in particular the corticosteroids - there's an axis called the hypothalamus pituitary adrenal axis, that controls corticosteroids and that may feedback to the hippocampus, result in a shrinkage and possibly result in depression.