Down syndrome: Neurons grown from stem cells show signature problems - Oxidative Stress

Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome.

Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects.

Anita Bhattacharyya

In new research published this week, Anita Bhattacharyya, a neuroscientist at the Waisman Center at the University of Wisconsin-Madison, reports on brain cells that were grown from skin cells of individuals with Down syndrome.

The research, published the week of May 27 in the Proceedings of the National Academy of Sciences (PNAS), was a basic exploration of the roots of Down syndrome.

"Even though Down syndrome is very common, it's surprising how little we know about what goes wrong in the brain," says Bhattacharyya. "These new cells provide a way to look at early brain development."

The study began when those skin cells were transformed into induced pluripotent stem cells, which can be grown into any type of specialized cell.

One significant finding was a reduction in connections among the neurons, Bhattacharyya says. "They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain."

Brain cells communicate through connections called synapses, and the Down neurons had only about 60 percent of the usual number of synapses and synaptic activity.

"This is enough to make a difference," says Bhattacharyya. "Even if they recovered these synapses later on, you have missed this critical window of time during early development."

The researchers looked at genes that were affected in the Down syndrome stem cells and neurons, and found that genes on the extra chromosome were increased 150 percent, consistent with the contribution of the extra chromosome.

However, the output of about 1,500 genes elsewhere in the genome was strongly affected. "It's not surprising to see changes, but the genes that changed were surprising," says Bhattacharyya.

The predominant increase was seen in genes that respond to oxidative stress, which occurs when molecular fragments called free radicals damage a wide variety of tissues.

"We definitely found a high level of oxidative stress in the Down syndrome neurons," says Bhattacharyya.

"This has been suggested before from other studies, but we were pleased to find more evidence for that. We now have a system we can manipulate to study the effects of oxidative stress and possibly prevent them."

Down syndrome includes a range of symptoms that could result from oxidative stress, Bhattacharyya says, including accelerated aging.

"In their 40s, Down syndrome individuals age very quickly. They suddenly get gray hair; their skin wrinkles, there is rapid aging in many organs, and a quick appearance of Alzheimer's disease. Many of these processes may be due to increased oxidative stress, but it remains to be directly tested."

Oxidative stress could be especially significant, because it appears right from the start in the stem cells.

"This suggests that these cells go through their whole life with oxidative stress," Bhattacharyya adds, "and that might contribute to the death of neurons later on, or increase susceptibility to Alzheimer's."

More information: Deficits in human trisomy 21 iPSCs and neurons,www.pnas.org/cgi/d… s.1216575110

Human cognition depends upon slow-firing neurons

Good mental health and clear thinking depend upon our ability to store and manipulate thoughts on a sort of "mental sketch pad."

In a new study, Yale School of Medicine researchers describe the molecular basis of this ability -- the hallmark of human cognition -- and describe how a breakdown of the system contributes to diseases such as schizophrenia and Alzheimer's disease.

Prof Amy Arnsten

"Insults to these highly evolved cortical circuits impair the ability to create and maintain our mental representations of the world, which is the basis of higher cognition," said Amy Arnsten, professor of neurobiology and senior author of the paper published in the Feb. 20 issue of the journal Neuron.

High-order thinking depends upon our ability to generate mental representations in our brains without any sensory stimulation from the environment.

These cognitive abilities arise from highly evolved circuits in the prefrontal cortex.

Mathematical models by former Yale neurobiologist Xiao-Jing Wang, now of New York University, predicted that in order to maintain these visual representations the prefrontal cortex must rely on a family of receptors that allow for slow, steady firing of neurons.

The Yale scientists show that NMDA-NR2B receptors involved in glutamate signaling regulate this neuronal firing.

These receptors, studied at Yale for more than a decade, are responsible for activity of highly evolved brain circuits found especially in primates.

Earlier studies have shown these types of NMDA receptors are often altered in patients with schizophrenia.

The Neuron study suggests that those suffering from the disease may be unable to hold onto a stable view of the world.

Also, these receptors seem to be altered in Alzheimer's patients, which may contribute to the cognitive deficits of dementia.

The lab of Dr. John Krystal, chair of the department of psychiatry at Yale, has found that the anesthetic ketamine, abused as a street drug, blocks NMDA receptors and can mimic some of the symptoms of schizophrenia.

The current study in Neuron shows that ketamine may reduce the firing of the same higher-order neural circuits that are decimated in schizophrenia.

"Identifying the receptor needed for higher cognition may help us to understand why certain genetic insults lead to cognitive impairment and will help us to develop strategies for treating these debilitating disorders," Arnsten said.

The above story is reprinted from materials provided by Yale University.

Autism: Mirror Neurons and Self-understanding

Recent findings are rapidly expanding researchers' understanding of a new class of brain cells, mirror neurons, which are active both when people perform an action and when they watch it being performed.

Some scientists speculate that a mirror system in people's 'perception' forms the basis for social behaviour, for our ability to imitate, acquire language, and show empathy and understanding.

It also may have played a role in the evolution of speech. Mirror neurons were so named because they fire, both when an animal acts and when it simply watches the same action. They were thought to "mirror" movement, as though the observer itself were acting.

Advances in the past few years have newly defined different types of mirror neurons in monkeys and shown how finely tuned these subsets of mirror neurons can be.

New studies also have further characterized both normal and abnormal, mirror activity in the brains of children with Autism, a social communication disorder, suggesting new approaches to treatment.

"The tremendous excitement that has been generated in the field by the study of mirror neurons stems from the implications of the findings, which have led to numerous new hypotheses about behavior, human evolution, and neuro-developmental disorders," says Mahlon DeLong, MD, of Emory University School of Medicine.

Mirror neurons, a class of nerve cells in areas of the brain relaying signals for planning movement and carrying it out, were discovered 11 years ago, an offshoot of studies examining hand and mouth movements in monkeys.

Mirror neuron research in the intervening years has expanded into a diverse array of fields and the implications have been enormous, encompassing; evolutionary development, theories of self and mind, and treatments for schizophrenia and stroke.

Findings include new research based on work in monkeys, showing that subsets of mirror neurons distinguish between observed actions carried out within hand's reach and those beyond the animal's personal space.

Read more of this article here: Mirror, Mirror In The Brain: Mirror Neurons, Self-understanding And Autism Research

Autism: Defective Genes May Explain Uncontrolled Brain Growth

As a baby grows inside the womb, its brain does not simply expand like a dehydrated sponge dropped in water.

Early brain development is an elaborate procession. Every minute some 250,000 neurons bloom, squirming past one another like so many schoolchildren rushing to their seats at the sound of the bell.

Each neuron grows a long root at one end and a crown of branches at the other, linking itself to fellow cells near and far.

By the end of the second trimester, neurons in the baby's brain have formed trillions of connections, many of which will not survive into adulthood—the least traveled paths will eventually wither.

Sometimes, the developing brain blunders, resulting in "neuro-developmental disorders," such as autism.

But exactly why or how early cellular mistakes cause autism has eluded medical science. Now, Eric Courchesne of the University of California, San Diego, thinks he has linked atypical gene activity to excessive growth in the autistic brain.

With the new data, he has started to trace a cascade of genetic and cellular changes that he thinks define autism.

Although intrigued by Courchesne's work, other researchers caution that explosive neural growth is not necessarily a defining feature of all autistic brains.

Since 1998 Courchesne has been searching autistic brains for unusual structural features.

His studies suggest that while in the womb, the autistic brain sprouts an excess of neurons and continues to balloon during the first five years of life, as all those extra neurons grow larger and form connections.

Sometime after age four or five, Courchesne has also found, autistic brains actually start to lose neural connections, faster than typical brains.

In a study published November 2011 in JAMA, The Journal of the American Medical Association, Courchesne reported that children with autism have 67 percent more neurons in their prefrontal cortex (PFC) than typical children.

Located in the area of the brain just behind the eyes, the PFC is responsible for what psychologists call "executive functions"—high-level thinking, such as planning ahead, inhibiting impulses and directing attention. In his 2011 study Courchesne sliced up brain tissue from six autistic children and seven typical children who had passed away and counted the number of cell bodies in the sections to estimate the total number of neurons in their PFCs.

Now, Courchesne and his colleagues have analyzed DNA and RNA in 33 cubes of brain tissue from people who passed away, 15 of whom were autistic (nine children and six adults) and 18 who had typical brains (seven children and 11 adults).

Looking at the order of DNA's building blocks reveals whether individual genes have mutations; measuring levels of RNA indicates how often those genes were translated into proteins.

Such gene expression, Courchesne and his colleagues found, varied between autistic and typical brains.

In brain tissue from both autistic children and autistic adults, genes coding for proteins that identify and repair mistakes in DNA were expressed at unusually low levels.

Additionally, all autistic brains demonstrated unusual activity levels for genes that determine when neurons grow and die and how newborn neurons migrate during early development.

Some genes involved in immune responses, cell-to-cell communication and tissue repair, however, were expressed at unusual levels in adult autistic brains, but not in autistic children's brains.

The results appear in the March 22 issue of PLoS Genetics.

You can also Read More of this article here at Scientific American: The Ballooning Brain

Research Claims Ritalin Improves Ability to Learn

Research Claims Ritalin Improves Ability to Learn

Ritalin (methylphenidate), a drug prescribed for millions of children who have attention deficit hyperactivity disorder (ADHD), appears to improve the ability to learn by enhancing the speed of learning. Currently, Ritalin is prescribed to help inhibit impulsive behaviour, which in turn can improve a child’s ability to focus on tasks.

The new finding is the result of research by investigators at the University of California, San Francisco (UCSF). It is significant because it lets scientists know that Ritalin impacts and improves behaviour through two specific types of neurotransmitter receptors rather than just one. Neurotransmitters are chemicals that act as messengers to allow neurons to communicate with each other.

Previously experts knew that Ritalin enhanced the activity of the neurotransmitter dopamine receptor known as D2, which controls the ability to stay focused on a task. The new research shows that another dopamine receptor called D1, which is involved in the ability to learn and learning efficiency, is also affected by Ritalin. Apparently the drug produces these benefits by strengthening the ability of the neurons to communicate with each other at their meeting points, called synapses.

These new findings may allow researchers to develop more efficient drugs to treat ADHD and to improve the ability to focus and learn more efficiently, according to Antonello Bonci, MD, principal investigator at the Ernest Gallo Clinic and Research Center and professor of neurology at UCSF.