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Autism 'begins long before birth'
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Ecoclimber
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New clue to autism found inside brain cells
Date:
March 26, 2014
Source: Washington University in St. Louis
Summary:
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers have learned. The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate's signal into messages traveling inside the cell.
Learning, social interactions and higher-level thinking in people with autism may be adversely affected by receptors inside brain cells, scientists at Washington University School of Medicine have learned. The type of receptor they studied glows green on the surface of this cell. Inside the cell, the receptor covers a membrane stained red.
Credit: Yuh-Jiin I. Jong
[Click to enlarge image]
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.
Scientists were already aware that the type of receptor in question was a potential contributor to these problems -- when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.
The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate's signal into messages traveling inside the cell.
In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.
Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells' volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.
"Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we're blocking all of this type of receptor, both inside and on the surface of the cell," said senior investigator Karen O'Malley, PhD, professor of neurobiology.
The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.
"The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there," said O'Malley. "But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell -- at least 50 percent, and in some cases as much as 90 percent -- that we wondered if the interior receptors had separate functions."
In earlier studies, O'Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.
The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O'Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.
When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.
In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O'Malley noted.
"This should be a factor we consider when we design drugs to target brain cell receptors," she said. "Do we want to reach cell surface receptors, receptors inside the cell or both?"
Story Source:
The above story is based on materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy. Note: Materials may be edited for content and length.
Journal Reference:
Date:
March 26, 2014
Source: Washington University in St. Louis
Summary:
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers have learned. The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate's signal into messages traveling inside the cell.
Learning, social interactions and higher-level thinking in people with autism may be adversely affected by receptors inside brain cells, scientists at Washington University School of Medicine have learned. The type of receptor they studied glows green on the surface of this cell. Inside the cell, the receptor covers a membrane stained red.
Credit: Yuh-Jiin I. Jong
[Click to enlarge image]
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.
Scientists were already aware that the type of receptor in question was a potential contributor to these problems -- when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.
The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate's signal into messages traveling inside the cell.
In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.
Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells' volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.
"Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we're blocking all of this type of receptor, both inside and on the surface of the cell," said senior investigator Karen O'Malley, PhD, professor of neurobiology.
The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.
"The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there," said O'Malley. "But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell -- at least 50 percent, and in some cases as much as 90 percent -- that we wondered if the interior receptors had separate functions."
In earlier studies, O'Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.
The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O'Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.
When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.
In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O'Malley noted.
"This should be a factor we consider when we design drugs to target brain cell receptors," she said. "Do we want to reach cell surface receptors, receptors inside the cell or both?"
Story Source:
The above story is based on materials provided by Washington University in St. Louis. The original article was written by Michael C. Purdy. Note: Materials may be edited for content and length.
Journal Reference:
- C. A. Purgert, Y. Izumi, Y.-J. I. Jong, V. Kumar, C. F. Zorumski, K. L. O'Malley. Intracellular mGluR5 Can Mediate Synaptic Plasticity in the Hippocampus. Journal of Neuroscience, 2014; 34 (13): 4589 DOI: 10.1523/JNEUROSCI.3451-13.2014
The qestion is why the overwhelming majority of autistic children are white boys. Other ethnic groups of boys and girls are much lower.
There's going to be a lot of politicol focus on autism in the next few months as the Combating Autism Act is coming up for funding shortly.
http://www.usatoday.com/story/news/nation/2014/03/27/autism-rates-rise/6957815/
There's going to be a lot of politicol focus on autism in the next few months as the Combating Autism Act is coming up for funding shortly.
http://www.usatoday.com/story/news/nation/2014/03/27/autism-rates-rise/6957815/
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Beyond
Juice Me Up, Scotty!!!
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Interesting remark liverock. I sense that solving the autism mystery holds part of the keys of future medicine.
Another big autism question... Do anyone knows if autism existed a century ago? Furthermore, has it in fact increased dramatically over time since getting the name/being observed? I admit this question is not easy and maybe impossible to respond, as one could argue that before autism the autists were clumpled in another psychiatric group but on the other hand autism is very well characterized.
lol Talking about solid hypothesis... One website is dedicated a how autism is caused by alien abductions who prefer caucasian males.
Another big autism question... Do anyone knows if autism existed a century ago? Furthermore, has it in fact increased dramatically over time since getting the name/being observed? I admit this question is not easy and maybe impossible to respond, as one could argue that before autism the autists were clumpled in another psychiatric group but on the other hand autism is very well characterized.
lol Talking about solid hypothesis... One website is dedicated a how autism is caused by alien abductions who prefer caucasian males.
caledonia
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poor methylation cycle genetics of the mother and father which are passed on to the baby + environmental factors in the womb and after birth, especially glutamate, mercury, low folate, etc. = autism
People with poor methylation tend to have high glutamate and low GABA anyway. Now add some more environmental glutamate from diet or vaccines. Glutamate kills brain cells.
Mercury isn't so hot either - that's another vicious cycle. People with poor methylation tend to accumulate mercury. The mother's mercury burden passes on to the baby. Vaccines contain more mercury in the form of thimersol.
People with poor methylation also tend to have lower folate and B12. Of course, folate is very important for the developing fetus. Doctors often give expectant mothers "folic acid" - if you have MTHFR mutations, you can't metabolize folic acid. It will be the same or even worse than not taking it.
The increase in glutamate, mercury and folic acid are all fairly recent phenomenon, coinciding with the rise of autism.
Notice that two of them are associated with vaccines which have been blamed on causing autism.
There may be other co-factors. There is no magic single source to point a finger at. Unfortunately, this is the nature of multifactorial disease, which makes it so hard to figure out.
"Early intervention" would start with the parents well before conception, and continue for years after the baby is born - not waiting until (oops!) the child has already developed autism.
=-==-=-=-=
There are 30 diseases caused by poor methylation (including ME/CFS), so presumably anyone with one of those 30 diseases (or a family history thereof) would be more likely to have a child with autism.
People with poor methylation tend to have high glutamate and low GABA anyway. Now add some more environmental glutamate from diet or vaccines. Glutamate kills brain cells.
Mercury isn't so hot either - that's another vicious cycle. People with poor methylation tend to accumulate mercury. The mother's mercury burden passes on to the baby. Vaccines contain more mercury in the form of thimersol.
People with poor methylation also tend to have lower folate and B12. Of course, folate is very important for the developing fetus. Doctors often give expectant mothers "folic acid" - if you have MTHFR mutations, you can't metabolize folic acid. It will be the same or even worse than not taking it.
The increase in glutamate, mercury and folic acid are all fairly recent phenomenon, coinciding with the rise of autism.
Notice that two of them are associated with vaccines which have been blamed on causing autism.
There may be other co-factors. There is no magic single source to point a finger at. Unfortunately, this is the nature of multifactorial disease, which makes it so hard to figure out.
"Early intervention" would start with the parents well before conception, and continue for years after the baby is born - not waiting until (oops!) the child has already developed autism.
=-==-=-=-=
There are 30 diseases caused by poor methylation (including ME/CFS), so presumably anyone with one of those 30 diseases (or a family history thereof) would be more likely to have a child with autism.
A.B.
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@caledonia
Mercury can damage neurons even at unexpectedly low concentrations by increasing glutamate levels.
http://link.springer.com/article/10.1007/BF02069504
Mercury can damage neurons even at unexpectedly low concentrations by increasing glutamate levels.
http://link.springer.com/article/10.1007/BF02069504
Vaccines are definitely a factor. A child today by 2 years old has had 26 vaccinations and there has been no research done, as far as I know, about the effect of so many vaccinations in such a short period of time on the childs immune or neurological systems.
Dr. Mercola has an interesting article on the rise in toxins in parents being handed down to children and being a cause of autism. It appears that an increase in toxins in parents has shown an increase of male genital malformations.
http://articles.mercola.com/sites/articles/archive/2014/04/02/environmental-toxin-exposure.aspx
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I would doubt that there would be any figures for "centuries" ago.
The word "spastic" covered many, many different conditions, folk with mental and/or physical difficulties which were badly understood, just got locked away in institutions and forgotten about.
Including members of the British royal family. There are cousins of the queen's who simply got locked away, disinherited and ignored because of their problems. It's only just come to light about this. Our so-called regal lot simply do not want to be associated with them.
The word "spastic" covered many, many different conditions, folk with mental and/or physical difficulties which were badly understood, just got locked away in institutions and forgotten about.
Including members of the British royal family. There are cousins of the queen's who simply got locked away, disinherited and ignored because of their problems. It's only just come to light about this. Our so-called regal lot simply do not want to be associated with them.
Hip
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Yes that's very true. The level of psychological sophistication was very poor centuries ago, and few if anyone would be able to discern and distinguish between all the various mental conditions that can befall an individual. The world's first psychology lab was set up not that long ago: in 1879 by Wilhelm Wundt in Germany; and the first detailed description of autism was only established in the 1940s; so it is unlikely that anyone would have been able to identify autism as a distinct condtion before that.
As peggy-sue says, the generic word "spastic" would likely have been applied to anyone with any mental or physical abnormalities. Since its relatively recent inception, the discipline of psychology has done an excellent job identifying and classifying the various mental health conditions and illness that can befall an individual.
Though with sophisticated psychological understanding of mental conditions only becoming available in the last 50 to 100 years, it does make you wonder what happened to individuals with severe conditions like autism centuries ago. Presumably just locked up somewhere, along with all the other "spastics".
The high prevalence of mental illness among royal families is almost certainly down to interbreeding. Marrying close relatives was common, in order to consolidate wealth and position.
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Hip
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When Generation Rescue, who always advocated the view that vaccinations are the cause of autism, commissioned a survey, they were shocked to discover that their survey found autism was more prevalent in the unvaccinated.
The survey discovered that 3% of all vaccinated children had an autism spectrum diagnosis, whereas for the unvaccinated children, the prevalence was 3.7%. (Sadly, because this result contradicted the political aims of Generation Rescue, they "spun" the result, and manipulated the data to make it look as if neurological conditions were more prevalent in the vaccinated, but this was just "spin".)
This survey result found by Generation Rescue makes sense if you subscribe to the theory that infectious pathogens may underlie many mental health conditions: because if you are vaccinated, you are more protected from such pathogens, so this may lower your chances of developing autism.
That is not to say that the anecdotal observations made by mothers that their child developed autism just hours after a vaccination are wrong. Remember that some vaccines contain live weakened (attenuated) versions of the pathogens they are trying to protect you from, so it is conceivable that these live attenuated versions may in some cases also precipitate autism. Or the immune boosting adjuvants incorporated into vaccines may play a role. But on average, the Generation Rescue survey indicates that vaccination is protective against autism (although the survey did not quite reach statistical significance).
I like the theory that some kind of predisposition towards autism arises from problems during pregnancy, as this thread discusses. Then once the stage is set for autism due to events taking place during gestation, any significant activation of the immune system in early life may trigger this latent autism.
It is known that if a mother catches influenza virus during the first trimester of pregnancy, this increases the risk that their child will develop schizophrenia later in life by 7 times (ref: 1). A similar thing may occur in autism.
So perhaps closer attention should be focused on what environmental toxins or infectious factors may be afflicting mothers during pregnancy which might later predispose the child to developing autism.
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Absolutely. Immune insult during pregnancy, coupled with gen susceptibility (and don't forget germline infections or other env insults), will skew the immune responses later on - so that the affected offspring will react to later immune stressors (vaccines being one) in abnormal ways, including excessive inflammation and impaired immune defences against live viruses (including vac strain ones). This has been shown many times in experimental animal studies. Meaning that this prenatal insult model does not rule out additional vaccine injury, on the contrary.
Real science desperately needed in that area, but unlikely to be funded any time soon
A link between immune dysfunction and autism is further exemplified by multi-genome analysis studies that found links between genes that are involved in inflammatory signalling and that predispose individuals to aberrant immune response to infections and risk of developing autism (Herbert et al. 2006; Saxena et al. 2012; Ziats and Rennert 2011), the findings of genomic associations between ASD and some autoimmune diseases like multiple sclerosis (Jung et al. 2011), as well as several findings from large European birth cohorts, which found perturbed immune responses and pro-inflammatory biomarkers in mothers and newborns who later develop autism (Abdallah et al. 2012; 2014; Brown et al. 2013; Zerbo et al. 2013).
In this context it must be mentioned that the most rigorous and largest population-based twin study of autism done to date has found that “susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component” and “although genetic factors also play an important role, they are of substantially lower magnitude than estimates from prior twin studies of autism.” (Hallmayer et al. 2011). Genetic variability likely pre-disposes for increased susceptibility to environmental challenges, as the only evidence, albeit limited, so far of autism genetic risk lies in immune-related genes (see above).
Findings of environmental pollution and significantly increased risk of autism also fit the above picture -- in addition to 'straighforward' mutagenic properties, exposure to various toxins primes/skews towards chronic pro-inflammatory states in both mothers and offspring ...
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