April 22, 2011 10:15 pm

Stem cells shed light on complex mental illness

 
Schizophrenic brain cells connecting with each other

Schizophrenic brain cells connect with each other less frequently than their healthy counterparts

Stem cell technology has been used to create and study living brain cells from patients with schizophrenia. Grown in laboratory dishes, these neurons make fewer nerve connections than those from healthy patients – though one drug used to treat schizophrenia reduces the abnormality.

Scientists at the Salk Institute in California and Penn State University reprogrammed skin cells from four patients to become induced pluripotent stem cells (iPSCs), an embryo-like state from which they were induced to grow into neurons.

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The study, published in Nature, illustrates how the transformation of skin via iPSCs into specialised “patient-specific” cells will give researchers a way to model diseases such as autism, bipolar disorder and schizophrenia in the lab.

“Schizophrenia exemplifies many of the research challenges posed by complex psychiatric disorders,” says Fred Gage, the project leader. “Without a basic understanding of the causes and the pathophysiology of the disorder, we lack the tools to develop effective treatments or take preventive measures.”

In most respects the neurons grown from healthy volunteers looked indistinguishable from those derived from schizophrenia patients. But when the scientists introduced a genetically modified rabies virus and watched it spread from neuron to neuron, they saw that the schizophrenic neurons connected less frequently with each other and had fewer projections growing from their cell bodies.

In addition, gene expression profiles identified almost 600 genes whose activity was misregulated in the schizophrenic neurons. Only 25 per cent of the genes had been implicated in schizophrenia before. The researchers then administered several antipsychotic medications to the cell cultures to test the drugs’ ability to improve neural connectivity. Only one, loxapine, increased the neurons’ ability to reach out and connect with their neighbours; it also affected the activity of hundreds of genes.

“These drugs are doing a lot more than we thought they were doing,” explains Salk researcher Kristen Brennand. “But now, for the very first time, we have a model system that allows us to study how antipsychotic drugs work in live, genetically identical neurons from patients with known clinical outcomes, and we can start correlating pharmacological effects with symptoms.”

Schizophrenia affects about 1 per cent of the population worldwide. “Nobody knows how much the environment contributes to the disease,” Brennand says. “By growing neurons in a dish, we can take the environment out of the equation, and start focusing on the underlying biological problems.”

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How antidepressants give us a lift

An important recent discovery in neuropharmacology is that antidepressants stimulate the production of new brain cells. The process, known as neurogenesis, provides a partial explanation of why the drugs lift the patient’s mood and why they take several weeks to become fully effective.

Now a stem cell study at the Institute of Psychiatry, part of King’s College London, has shown how antidepressants make new neurons. It turns out that they activate a key protein involved in the brain’s response to stress, which is called the glucocorticoid receptor.

The researchers used a culture of hippocampal stem cells supplied by ReNeuron, a UK stem cell company. These cells are the main source of new neurons in the human brain.

“For the first time in a clinically relevant model, we were able to show that antidepressants produce more stem cells and also accelerate their development into adult brain cells,” says Christoph Anacker, lead author of the study, published in the journal Molecular Psychiatry. “Additionally, we demonstrated for the first time that stress hormones, which are generally very high in depressed patients, show the opposite effect.”

Antidepressants activate the glucocorticoid receptor, which switches on particular genes that turn immature stem cells into adult neurons.

“By increasing the number of newborn cells in the adult human brain, antidepressants counteract the damaging effects of stress hormones and may overcome the brain abnormalities which may cause low mood and impaired memory in depression,” says Anacker.

The researchers will now be able to test new drug candidates for their effect on the glucocorticoid receptor and their efficiency in stimulating neurogenesis, in the hope of developing more effective, better targeted antidepressants.

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How do insects walk upside down?

Many insects, spiders and lizards have arrays of fine adhesive hairs or “setae” on their foot pads, which enable them to climb almost any natural surface. So far scientists have focused mainly on the sticky feet of geckos, but now zoologists at Cambridge University have turned their attention to leaf beetles.

The green dock beetle has three distinct shapes of setae – pointed, flat and disc-like – arranged in specific patterns across its feet. All three types are required for the insects both to adhere to shiny leaf surfaces and to peel their feet away when they need to move around.

The Cambridge study, published in the journal Naturwissenschaften (The Nature of Science), reports the first adhesive force measurements from single microscopic hairs in a live animal. There was no existing technique for determining the individual properties of the tiny setae, so the researchers devised a method for measuring their stickiness in a live beetle, using a fine glass cantilever.

The results showed that the disc-like hairs stuck most tightly, followed by spatula-tipped and then pointed hairs. Disc-like hairs were also stiffer than the other types, probably to give stability to the footpad. These hairs seem to allow beetles to achieve strong adhesion on smooth surfaces. This ability is important for the males to hold on to the back of the females during mating. The other hair types, being easier to unstick, may help the beetle to detach its feet rapidly when running upside down.

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Telescopes zoom in on cosmic history

Astronomers have discovered that the first galaxies were born unexpectedly early in cosmic history, just 200 million years after the Big Bang 13.7 billion years ago.

The discovery was made with three telescopes – Hubble and Spitzer in space, and Keck on Hawaii. The international observing team used the “gravitational lensing” effect. An extremely faint and distant galaxy that would otherwise be too faint to see, even with the most powerful telescope, was made visible by the gravity of a cluster of alaxies that happened to lie between it and Earth. This bent and focused the light rays on their way to us.

Although the galaxy in question was observed at an age of 950 million years – not the oldest on record – analysis of the stars within it showed that some of these were already 750 million years old, implying that it must have formed when the universe was only 200 million years old.

“It seems probable that there are in fact far more galaxies out there in the early universe than we previously estimated – it’s just that many galaxies are older and fainter, like the one we have just discovered,” says Jean-Paul Kneib of the Laboratoire d’Astrophysique de Marseille.

The discovery might explain one mystery: how the fog of hydrogen gas, which would have made the early universe opaque to ultraviolet light, cleared. Radiation from a previously unsuspected plethora of young galaxies could have done the trick.

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