Drug Treatment Corrects Autism Symptoms in Mouse Model
Autism results from abnormal cell communication. Testing a new theory, researchers at the University of California, San Diego School of Medicine have used a newly discovered function of an old drug to restore cell communications in a mouse model of autism, reversing symptoms of the devastating disorder.
The findings are published in the March 13, 2013 issue of the journal PLOS ONE.
“Our (cell danger) theory suggests that autism happens because cells get stuck in a defensive metabolic mode and fail to talk to each other normally, which can interfere with brain development and function,” said Robert Naviaux, MD, PhD, professor of medicine and co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego. “We used a class of drugs that has been around for almost a century to treat other diseases to block the ‘danger’ signal in a mouse model, allowing cells to return to normal metabolism and restore cell communication.”
“Of course, correcting abnormalities in a mouse is a long way from a cure for humans,” said Naviaux, “but we are encouraged enough to test this approach in a small clinical trial of children with autism spectrum disorder in the coming year. This trial is still in the early stages of development. We think this approach – called antipurinergic therapy or APT – offers a fresh and exciting new path that could lead to development of a new class of drugs to treat autism.”
Autism spectrum disorders (ASDs) are complex disorders defined by abnormalities in the development of language, social and repetitive behaviors. Hundreds of different genetic and environment factors are known to confer risk. In this study, nearly a dozen UC San Diego scientists from different disciplines collaborated to find a unifying mechanism that explains autism. Their work is the result of one of just three international “Trailblazer” awards given by the group Autism Speaks in 2011.
Describing a completely new theory for the origin and treatment of autism using APT, Naviaux and colleagues introduce the concept that a large majority of both genetic and environmental causes for autism act by producing a sustained cell danger response – the metabolic state underlying innate immunity and inflammation.
“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated,” Naviaux explained. “This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.”
Since mitochondria – the so-called “power plants” of the cell – play a central role in both infectious and non-infectious cellular stress, innate immunity and inflammation, Naviaux and colleagues searched for a signaling system in the body that was both linked to mitochondria and critical for innate immunity. They found it in extracellular nucleotides like adenosine triphosphate (ATP) and other mitokines – signaling molecules made by distressed mitochondria. These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body. Fifteen types of purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism.
The researchers tested suramin – a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916 – in mice. They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms. The drug restored 17 types of multi-symptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination and normalizing mitochondrial metabolism.
“The striking effectiveness shown in this study using APT to ‘reprogram’ the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders,” Naviaux said.
![In this schematic, reduced activation in discrete medial prefrontal brain regions is depicted (in blue) in schizophrenia patients, occurring 0.2 seconds after sound changes (top panel), cascading forward to widespread brain regions associated with the automatic activation of attentional networks 0.1 second later (bottom panel).
In Schizophrenia Patients, Auditory Cues Sound Bigger Problems
Researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System have found that deficiencies in the neural processing of simple auditory tones can evolve into a cascade of dysfunctional information processing across wide swaths of the brain in patients with schizophrenia.
The findings are published in the current online edition of the journal Neuroimage.
Schizophrenia is a mental disorder characterized by disturbed thought processes and difficulty in discerning real from unreal perceptions. Common symptoms include auditory hallucinations and unfounded suspicious ideas. The disorder affects about 1 percent of the U.S. population, or roughly 3 million people.
“Impairments in the early stages of sensory information processing are associated with a constellation of abnormalities in schizophrenia patients,” said Gregory Light, PhD, associate professor of psychiatry at UC San Diego and senior author of the study.
These impairments, according to Light, may explain how schizophrenia patients develop clinical symptoms such as hearing voices that others cannot hear and difficulty with cognitive tasks involving attention, learning and recalling information. “If someone’s brain is unable to efficiently detect subtle changes in sounds despite normal hearing, they may not be able to automatically direct their attention and rapidly encode new information as it is being presented.”
Light and colleagues used electroencephalography – a technique that records patterns of electrical brain activity using electrodes positioned on the scalp – on 410 schizophrenia patients and 247 nonpsychiatric comparison subjects. The researchers employed novel computational imaging approaches to deconstruct the brain dynamics that underlie two leading neurobiological markers used in schizophrenia research: mismatch negativity (MMN) and P3a event-related potentials.
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In healthy volunteers, a specific pattern of EEG responses across a complex network of brain structures is elicited within a fraction of a second in response to changes in auditory tones. In patients with schizophrenia, the researchers found that this normal process is disrupted. Reduced activity in specific areas of the medial frontal lobe quickly propagated to other regions of the brain that support activation of attentional networks.
“Changes in the tone of speech convey complex information including nuances of emotional meaning and content,” said Light, who is also associate director of the VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC) at the San Diego VA Medical Center. “If a patient’s brain is not processing auditory information optimally, he or she may miss out on important-but-subtle social cues and other critical information. They may not properly recognize sarcasm or humor that is carried by pitch changes in speech. This can be a major barrier to achieving better functioning in social relationships, school or job performance, and ultimately limit their overall quality of life.”
In research published earlier this year, Light and colleagues established that MMN and P3a showed promise for unlocking the elusive brain and molecular dysfunctions of schizophrenia patients. “These brain-based biomarkers may eventually prove to be useful for assisting clinicians with diagnosis, guiding treatment decisions, and tracking therapeutic response over time. These measures may also predict which individuals are at risk for developing a serious mental illness and are most likely to benefit from course-altering early interventions.”
According to Stephen R. Marder, MD, VISN-22 MIRECC director and a professor at UCLA’s Semel Institute for Neuroscience and Human Behavior, “this study makes a valuable contribution to our understanding of how impairments in the very early processing of sensory information in schizophrenia can explain the complex symptoms of the illness. This new knowledge may also be useful in developing better pharmacological and non-pharmacological treatments for schizophrenia.”](http://24.media.tumblr.com/tumblr_mebkvcCIBD1qievavo1_1280.jpg)
In this schematic, reduced activation in discrete medial prefrontal brain regions is depicted (in blue) in schizophrenia patients, occurring 0.2 seconds after sound changes (top panel), cascading forward to widespread brain regions associated with the automatic activation of attentional networks 0.1 second later (bottom panel).
In Schizophrenia Patients, Auditory Cues Sound Bigger Problems
Researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System have found that deficiencies in the neural processing of simple auditory tones can evolve into a cascade of dysfunctional information processing across wide swaths of the brain in patients with schizophrenia.
The findings are published in the current online edition of the journal Neuroimage.
Schizophrenia is a mental disorder characterized by disturbed thought processes and difficulty in discerning real from unreal perceptions. Common symptoms include auditory hallucinations and unfounded suspicious ideas. The disorder affects about 1 percent of the U.S. population, or roughly 3 million people.
“Impairments in the early stages of sensory information processing are associated with a constellation of abnormalities in schizophrenia patients,” said Gregory Light, PhD, associate professor of psychiatry at UC San Diego and senior author of the study.
These impairments, according to Light, may explain how schizophrenia patients develop clinical symptoms such as hearing voices that others cannot hear and difficulty with cognitive tasks involving attention, learning and recalling information. “If someone’s brain is unable to efficiently detect subtle changes in sounds despite normal hearing, they may not be able to automatically direct their attention and rapidly encode new information as it is being presented.”
Light and colleagues used electroencephalography – a technique that records patterns of electrical brain activity using electrodes positioned on the scalp – on 410 schizophrenia patients and 247 nonpsychiatric comparison subjects. The researchers employed novel computational imaging approaches to deconstruct the brain dynamics that underlie two leading neurobiological markers used in schizophrenia research: mismatch negativity (MMN) and P3a event-related potentials.
Neural Stem Cells Regenerate Axons in Severe Spinal Cord Injury
New relay circuits, formed across sites of complete spinal transaction, result in functional recovery in rats
In a study at the University of California, San Diego and VA San Diego Healthcare, researchers were able to regenerate “an astonishing degree” of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS).
The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. The work will be published in the journal Cell on September 14.
(For a history of spinal cord repair science and the significance of this latest work, read Ohio State University neuroscientist Phillip Popovich’s review here.)
The UC San Diego-led team embedded neural stem cells in a matrix of fibrin (a protein key to blood-clotting that is already used in human neuron procedures), mixed with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords.
“Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before,” said Mark Tuszynski, MD, PhD, professor in the UC San Diego Department of Neurosciences and director of the UCSD Center for Neural Repair, who headed the study. “The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement.”
In addition, adult cells above the injury site regenerated into the neural stem cells, establishing a new relay circuit that could be measured electrically. “By stimulating the spinal cord four segments above the injury and recording this electrical stimulation three segments below, we detected new relays across the transaction site,” said Tuszynski.
To confirm that the mechanism underlying recovery was due to formation of new relays, when rats recovered, their spinal cords were re-transected above the implant. The rats lost motor function – confirming formation of new relays across the injury.
The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 – a score reflecting the animals’ ability to move all joints of affected legs.
Results were then replicated using two human stem cell lines, one already in human trials for ALS. “We obtained the exact results using human cells as we had in the rat cells,” said Tuszynski.
The study made use of green fluorescent proteins (GFP), a technique that had never before been used to track neural stem cell growth. “By tagging the cells with GFP, we were able to observe the stem cells grow, become neurons and grow axons, showing us the full ability of these cells to grow and make connections with the host neurons,” said first author Paul Lu, PhD, assistant research scientist at UCSD’s Center for Neural Repair. “This is very exciting, because the technology didn’t exist before.”
Pictured: Artist’s rendering of neurons
Color-coded representations of human and mouse brains show similarities in cortical functional organization, with some variance according to species-specific needs. F/M indicates the frontal/motor cortex; S1, primary somatosensory cortex; A1, auditory cortex and V1, visual cortex.
Of Mice and Men, a Common Cortical Connection
MRI study finds genetic basis of brain development largely similar in mice and humans
A new study using magnetic resonance imaging data of 406 adult human twins affirms the long-standing idea that the genetic basis of human cortical regionalization – the organization of the outer brain into specific functional areas – is similar to and consistent with patterns found in other mammals, indicating a common conservation mechanism in evolution.
The findings by researchers at the University of California, San Diego School of Medicine and colleagues are published in the November 17 issue of the journal Neuron.
Past animal studies, primarily in rodents, have shown that development of distinct areas of the cortex – the outer layer of the brain – is influenced by genes exhibiting highly regionalized expression patterns. The new study is among the first to confirm these findings using data from human subjects. As in other mammals, the researchers found that that genetic influences in human brain development progress along a graduating scale anterior-to-posterior (front-to-back) in a bilateral, symmetric pattern.
There were, of course, differences based upon the particular needs and functions of each species.
Catching Signs of Autism Early: the One-Year Well-Baby Check-Up Approach
A novel strategy developed by autism researchers at the University of California, San Diego School of Medicine, called “The One-Year Well-Baby Check Up Approach,” shows promise as a simple way for physicians to detect cases of Autism Syndrome Disorder (ASD), language or developmental delays in babies at an early age.
Led by Karen Pierce, PhD, assistant professor in the UC San Diego Department of Neurosciences, researchers at the UC San Diego Autism Center of Excellence (ACE) assembled a network of 137 pediatricians in the San Diego region and initiated a systematic screen program for all infants at their one-year check up. Their study will be published in the April 28online edition of the Journal of Pediatrics.
“There is extensive evidence that early therapy can have a positive impact on the developing brain,” said Pierce. “The opportunity to diagnose and thus begin treatment for autism around a child’s first birthday has enormous potential to change outcomes for children affected with the disorder.”
Ferguson’s ability to remember the cities she’s lived in, jobs she’s worked and, yes, all the men she’s married, makes her very valuable to Jacopo Annese, a neuroanatomist at the University of California, San Diego. Annese is director of The Brain Observatory, a research center at UCSD where brains are sliced up, laid out on slides and then scanned into digital images, which researchers can use to visualize what a variety of brains look like. Scientists can use Annese’s images to see how diseases like Alzheimer’s physically change the brain.
Annese became well-known for his work with Henry Molaison, a famous amnesiac whose brain images will be studied by scientists across the world for insights into memory impairment.
“The Few, the Proud, the Brain Donors” (Voice of San Diego)
