Impaired Synapse 'Pruning' Linked to Autism
Medscape Medical News
August 22, 2014
The brain's normal process of "pruning" bursts of excessive neural synapses that occur during development is impaired in children and adolescents with autism, and the defect appears to be linked to the overexpression of a key enzyme, new research shows.
In addition, preliminary findings suggest that it may be possible to treat this phenomenon using an immunosuppressant commonly used in transplant patients.
"We know that autism is linked to a wide range of genetic and probably some environmental factors, but the finding of this biological correlate that there is less pruning of synapses in people with autism is novel," coinvestigator David Sulzer, PhD, told Medscape Medical News.
"Additionally, we have identified a potentially important mechanism, which, in the mouse models that we investigated, appears to involve the overactivation of the enzyme mTOR," said Dr. Sulzer, a professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University Medical Center in New York City.
The study was published online August 21 in Neuron.
Postmortem Study
During development, the brain forms synapses, sometimes in excess, as it assembles neural circuits. However, synaptic elimination, or pruning, goes into effect, keeping the formation in check, the authors explained.
"[Postnatal] synapse formation exceeds pruning at early ages, yielding excessive excitatory synapses essential for the assembly of neural circuits," the investigators write.
"Synaptic elimination subsequently outpaces formation, resulting in net spine pruning from childhood through adolescence," they add.
Researchers have meanwhile recently shown that people with autism have an abundance of excitatory synapses in the cerebral cortex, compared with those without autism (Hutsler JJ, et al. Brain Res. 1309,83?94).
In seeking to better understand this mechanism, Dr. Sulzer and his colleagues evaluated the postmortem brains of 13 autistic children aged 2 to 9 years who had died from other causes and compared them with 22 brains from children who had been without autism.
They found that by late childhood, although normal brains had succeeded in pruning as much as 50% of the spine's dendritic density, the density of brains of children with autism was reduced only by 16%.
The autistic children's brain cells were found to be packed with old and damaged components that had not been cleared out through autophagy, or the degradation of unnecessary components.
The researchers further found in mouse models a correlation between an overexpression of the enzyme mTOR, which is linked to normal autophagy, and a higher dendritic density.
Likewise, high levels of overactive mTOR were found in most of the brains of the autistic children.
Potential Treatment?
The drug rapamycin (Rapamune, PF Prism CV), used for immunosuppression in transplantation, inhibits mTOR overexpression. To evaluate its potential in autism, Dr. Sulzer and his team treated the mice with the drug. They found it to be effective not just in improving the pruning effect but also, importantly, in correcting autismlike behaviors even after they had developed.
The drug has side effects that would prevent its use for autism in humans, but its efficacy in mice suggests potential benefits in the development of a drug focusing on the same or similar targets, Dr. Sulzer said.
"It looks like we've uncovered a very important step in the development of autism, and the findings are promising for treatment of the disease because they show us specific steps for potential treatment of the disorder ― even after it's diagnosed," he added.
"While rapamycin has side effects, we could possibly tailor a drug to act further downstream, for instance, targeting the autophagy for synaptic pruning."
Dr. Sulzer was cautious in his optimism, however, noting that much more needs to be understood about the mechanisms.
"This is clearly unlikely to be the whole picture ― I don't think synaptic pruning will tell the whole story, and I don't think it will hold up in every patient with autism," he said.
"There will certainly be other very important aspects, but nevertheless, this could be a convergent aspect of the disorder."
Valuable Contribution
Commenting on the research for Medscape Medical News, neurologist Judy Willis, MD, who is based in Santa Barbara, California, agreed that the findings raise potentially important therapeutic possibilities.
"Although not appropriate for children with autism, the [rapamycin] benefit in mice is encouraging for further research with other medications in the class of drugs that reduce the immune response," she told Medscape Medical News.
Although the study involved brain material from autopsies, "now that the protein has been found with the high association to the pathological increase in the amount of mTOR in the brains of children with autism, further research can be directed toward finding in vivo measures of this protein to aid in the early diagnosis of autism such that as medical interventions become available, their use can be guided by evidence of elevated levels."
She added that the study represents a valuable contribution to evidence on the causes behind autism.
"By linking the disrupted mTOR quantities with the decreases in cellular debris cleanup ― seen in increased dendritic spines ― we are now a step closer in the search for a common genetic control mechanism involved in autism spectrum disorder synaptic pathology."
Neuron. Published online August 21, 2014. Abstract
Medscape Medical News
August 22, 2014
The brain's normal process of "pruning" bursts of excessive neural synapses that occur during development is impaired in children and adolescents with autism, and the defect appears to be linked to the overexpression of a key enzyme, new research shows.
In addition, preliminary findings suggest that it may be possible to treat this phenomenon using an immunosuppressant commonly used in transplant patients.
"We know that autism is linked to a wide range of genetic and probably some environmental factors, but the finding of this biological correlate that there is less pruning of synapses in people with autism is novel," coinvestigator David Sulzer, PhD, told Medscape Medical News.
"Additionally, we have identified a potentially important mechanism, which, in the mouse models that we investigated, appears to involve the overactivation of the enzyme mTOR," said Dr. Sulzer, a professor of neurobiology in the departments of psychiatry, neurology, and pharmacology at Columbia University Medical Center in New York City.
The study was published online August 21 in Neuron.
Postmortem Study
During development, the brain forms synapses, sometimes in excess, as it assembles neural circuits. However, synaptic elimination, or pruning, goes into effect, keeping the formation in check, the authors explained.
"[Postnatal] synapse formation exceeds pruning at early ages, yielding excessive excitatory synapses essential for the assembly of neural circuits," the investigators write.
"Synaptic elimination subsequently outpaces formation, resulting in net spine pruning from childhood through adolescence," they add.
Researchers have meanwhile recently shown that people with autism have an abundance of excitatory synapses in the cerebral cortex, compared with those without autism (Hutsler JJ, et al. Brain Res. 1309,83?94).
In seeking to better understand this mechanism, Dr. Sulzer and his colleagues evaluated the postmortem brains of 13 autistic children aged 2 to 9 years who had died from other causes and compared them with 22 brains from children who had been without autism.
They found that by late childhood, although normal brains had succeeded in pruning as much as 50% of the spine's dendritic density, the density of brains of children with autism was reduced only by 16%.
The autistic children's brain cells were found to be packed with old and damaged components that had not been cleared out through autophagy, or the degradation of unnecessary components.
The researchers further found in mouse models a correlation between an overexpression of the enzyme mTOR, which is linked to normal autophagy, and a higher dendritic density.
Likewise, high levels of overactive mTOR were found in most of the brains of the autistic children.
Potential Treatment?
The drug rapamycin (Rapamune, PF Prism CV), used for immunosuppression in transplantation, inhibits mTOR overexpression. To evaluate its potential in autism, Dr. Sulzer and his team treated the mice with the drug. They found it to be effective not just in improving the pruning effect but also, importantly, in correcting autismlike behaviors even after they had developed.
The drug has side effects that would prevent its use for autism in humans, but its efficacy in mice suggests potential benefits in the development of a drug focusing on the same or similar targets, Dr. Sulzer said.
"It looks like we've uncovered a very important step in the development of autism, and the findings are promising for treatment of the disease because they show us specific steps for potential treatment of the disorder ― even after it's diagnosed," he added.
"While rapamycin has side effects, we could possibly tailor a drug to act further downstream, for instance, targeting the autophagy for synaptic pruning."
Dr. Sulzer was cautious in his optimism, however, noting that much more needs to be understood about the mechanisms.
"This is clearly unlikely to be the whole picture ― I don't think synaptic pruning will tell the whole story, and I don't think it will hold up in every patient with autism," he said.
"There will certainly be other very important aspects, but nevertheless, this could be a convergent aspect of the disorder."
Valuable Contribution
Commenting on the research for Medscape Medical News, neurologist Judy Willis, MD, who is based in Santa Barbara, California, agreed that the findings raise potentially important therapeutic possibilities.
"Although not appropriate for children with autism, the [rapamycin] benefit in mice is encouraging for further research with other medications in the class of drugs that reduce the immune response," she told Medscape Medical News.
Although the study involved brain material from autopsies, "now that the protein has been found with the high association to the pathological increase in the amount of mTOR in the brains of children with autism, further research can be directed toward finding in vivo measures of this protein to aid in the early diagnosis of autism such that as medical interventions become available, their use can be guided by evidence of elevated levels."
She added that the study represents a valuable contribution to evidence on the causes behind autism.
"By linking the disrupted mTOR quantities with the decreases in cellular debris cleanup ― seen in increased dendritic spines ― we are now a step closer in the search for a common genetic control mechanism involved in autism spectrum disorder synaptic pathology."
Neuron. Published online August 21, 2014. Abstract
