Antidepressants shown to nurture neurons

Yale scientists find that a growth-inducing protein plays a role in fighting mood disorders.

Doctors warn patients starting on antidepressants that they will have to wait weeks for the effects to kick in. Marketing materials for the drugs claim that the medications correct imbalances of neurotransmitters in the brain. So why must patients wait?

That lag time sparked the curiosity of Ronald S. Duman, Ph.D., the Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology. It was clear, he said, that the drugs’ effects on neurotransmitter levels cannot fully explain why the drugs can help relieve depression. “You have to wait for something else to happen,” says Duman.

Duman and graduate student Jennifer L. Warner-Schmidt have now shown that the “something else” can be attributed in part to a growth-inducing protein called vascular endothelial growth factor (VEGF). In a March 13 article in the Proceedings of the National Academy of Sciences, they reported that the neurotrophin VEGF is necessary for antidepressants to work in preclinical models.

In previous rodent studies, Duman had found that sustained use of antidepressants and electroconvulsive therapy (ECT) causes new cells to proliferate in the hippocampus, a brain structure that plays a vital role in memory, emotion and learning. The hippocampus shrinks under long-term stress, and Duman showed that by spurring the growth of new neurons, antidepressant drugs reverse or block the effects of stress on the hippocampus.

Duman and Warner-Schmidt have now linked VEGF to neurogenesis in the hippocampus. They showed that two classes of antidepressants and ECT increase the levels of VEGF, while blocking the effects of VEGF thwarted neurogenesis in the hippocampus.

“Neurogenesis has become very interesting,” said Duman. “Even the idea that you can make new neurons is exciting, and we think that neurotrophins contribute to the effects of antidepressants.”

Duman said that VEGF and at least one other neuronal growth factor, brain-derived neurotrophic factor, are necessary not only to allow neurogenesis but also to support the function of mature neurons. “Trophic factors are not just necessary for survival,” he said. “They are also required for growth, and closely involved in normal function.”

Still, Duman said, his discovery of the role of neurotrophins “is probably not the whole story. You can’t explain the entire action of antidepressants through neurotrophins and neurogenesis.” In the meantime, this new information about VEGF might provide new pathways for antidepressant therapies.

—Cathy Shufro

Cyclic AMP, a molecule linked to stress, also plays a role in memory loss

Working memory, the sticky-note reminder system of the brain, holds on to temporarily needed information by forming transient neural networks that keep firing even as the brain ponders other matters. That way the message persists despite distractions. Unless, of course, the network is broken—in which case that mental note to pick up your dry cleaning after work vanishes into your cerebral ether.

After two years of experimentation in three animal models, Yale researchers led by Amy F.T. Arnsten, Ph.D., professor of neurobiology, have identified the molecular mechanism that can make or break a neural network representing a short-term memory. These findings open the door to understanding what causes cognitive function to falter and how to treat several mental disorders.

They found that a molecule called cyclic adenosine monophosphate (cAMP), which accumulates in times of stress and in the brains of persons with certain mental disorders, disconnects the neural networks in the prefrontal cortex by forcing open certain ion channels, much like tripping a circuit breaker to halt the flow of electricity. To keep the networks functioning, these channels, called hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, must remain closed. They get some help from another type of molecule found next to HCN channels, the alpha 2A adrenoceptor, which, when activated, strengthens the neural networks and keeps them connected by preventing cAMP production.

Alpha 2A adrenoceptors are naturally stimulated by the neurotransmitter norepinephrine, but medications like guanfacine, an antihypertensive agent, also activate them, as the Yale group showed in their paper published in April in the journal Cell. It has long been known that guanfacine can improve the performance of working memory, and the drug is now being used to treat several prefrontal cortical disorders, but how it works has remained a mystery until now. Spurred by intriguing data from the lab of David A. McCormick, Ph.D., professor of neurobiology, the group began to explore the role of HCN channels. “This is an extraordinary example of knowing how a drug works all the way to the level of an ion channel,” said Arnsten.

Excessive HCN channel opening, she said, likely underlies lapses in cognitive function caused by stress, normal aging and several mental disorders, including attention-deficit hyperactivity disorder (ADHD), schizophrenia and bipolar disorder.

With this new finding, researchers can now pursue drug therapies for memory-related disorders involving the prefrontal cortex.

—Kara A. Nyberg

et cetera

Chlamydia more prevalent

Young women between the ages of 14 and 19 are getting infected and reinfected with chlamydia at a rate higher than previously reported, according to a study published in the Archives of Pediatrics and Adolescent Medicine in March.

Linda M. Niccolai, Ph.D., assistant professor of epidemiology (microbial diseases), tracked 411 young women over four years. More than half were diagnosed with the sexually transmitted disease and almost 30 percent reported repeated infections. Niccolai attributed the high rate of recurrent infection to multiple sex partners, lack of condom use and inadequate treatment of the young women’s sex partners.

Niccolai said it is important to educate and counsel patients at the time of the initial diagnosis.“It is possible that young women think chlamydia is ‘no big deal’ because it is easily treated with a single dose of oral antibiotics,” she said. Untreated, however, chlamydia can lead to pelvic inflammatory disease, complications of pregnancy, and sterility or reactive arthritis in men.

—John Curtis

A superbug from Iraq

Wounded soldiers returning from Iraq in the fall of 2006 were found to be carrying a “superbug” responsible for highly drug-resistant infections that spread rapidly in hospitals. The culprit is A. baumannii, a bacterium that causes pneumonia, meningitis, septicemia and urinary tract infections. Using a new and rapid method called high-density pyrosequencing, Yale researchers sequenced the bacterium’s genome to learn how it functions, according to a report in the March 1 issue of Genes and Development. Analysis revealed that 17.2 percent of the bacterium’s DNA that codes for protein is located in 28 so-called alien islands, sequences that originated in other micro-organisms.

“Drug-resistant bacterial infections are a rapidly growing problem in hospital settings, and now in difficult conditions of combat,” said principal investigator Michael Snyder, Ph.D., the Lewis B. Cullman Professor of Molecular, Cellular and Developmental Biology. “Having the genome sequence of this microbe is critical for understanding how it harms humans.”

—J. C.


			Originally published in Yale Medicine, Autumn 2007. Copyright © 2007 Yale University School of Medicine. All rights reserved.