Creatine, the Sub-types of Autism is Affects, and the Missing $26 million

Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.

 

 

Gene-based Autism Research

Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine

Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.

Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.

We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
 

Creatine Deficiency

Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
 

Disorders of Creatine transport and metabolism

 

1.      AGAT 

AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.

For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.

You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.

http://epiphanyasd.blogspot.com/2013/11/central-serotonergic-hypoactivity-in_4.html

One particular paper was:-

Decreased tryptophan metabolism in patients with autism spectrum disorders

2.     GAMT

GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

Treatment

If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
 

3.     X-linked Creatine deficiency

The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.

To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-

$26 million and three more years

Here is the official report from the University:- 

Cyclocreatine Normalizes Cognition in Creatine Deficient Mouse

 

Peter’s thoughts on Creatine

I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.

Stimulators of growth hormone (GH) secretion include:

• peptide hormones
• GHRH  through binding to the growth hormone-releasing hormone receptor
• ghrelin through binding to growth hormone secretagogue receptors
• sex hormones
• increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
• estrogen
• clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

• hypoglycemia, arginine and propranolol by inhibiting somatostatin release
• deep sleep
• niacin as nicotinic acid (Vitamin B3)
• fasting
• vigorous exercise

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 

Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.

 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.

If you live in the Big Apple:-

Where Can I Get Testing?

The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.

If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.

Conclusion

Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.

 

Why Girls don’t get Mild Autism and Why Alpha Females may have Kids with Autism.

You may or may not have seen the 2006 comedy film Borat; it was critically acclaimed in the US, but took a bit of time to become a commercial hit.  It brought to public attention its writer, producer and leading man, Sacha Baron Cohen.

Ted, aged 13 and very neurotypical, is a fan of Borat.

In the autism research community, Sacha’s brother Simon is equally well known.  He is the Director of the Cambridge University's Autism Research Centre and a Fellow of Trinity College.

All very interesting,  Ted’s Grandfather also went to Trinity College Cambridge.  Ted’s brother, Monty aged 10 with ASD, has yet to produce a movie, but he has helped to produce an autism blog.    

As you may have noted on this blog, I am rather disappointed with the autism research coming out of the United Kingdom.  90% of the good stuff is from the US.

The extreme male brain theory of autism

One of the well-known autism theories is from Simon Baron-Cohen, it is called:-

The extreme male brain theory of autism

Simon has been developing his theory that something called “assortative mating” may be at least partly to blame for the spectacular rise in autism diagnoses.

The theory states that when people with strongly “systemising” personalities – the sort of people who become engineers, doctors and computer experts – marry each other and produce children, the effects of this kind of “male brain” are genetically magnified, increasing the chances of producing an autistic child – a child with what Simon suspects is an “extreme male brain”.

Strong “systemisers” are often slightly obsessive, perfectionist and make great scientists and are often extremely talented at music. But they sometimes have difficulties socially interacting with other people – a combination of traits that can blend into the milder end of the autism spectrum.

Some of the sharpest increases in autism diagnoses have been found in Silicon Valley, home to perhaps the largest population of successful systemisers on Earth. Tens of thousands of technicians, engineers and programmers work in the computer industry;  inevitably, many of these people marry each other.

Until relatively recently, being exceptionally bright was not much use to you if you were female. The opportunities for a woman to earn her living through brainpower alone were extremely limited. You could be a teacher, or perhaps, if you were lucky, a doctor.

Going to university was difficult and expensive; most did not even allow girls to study. There were certainly few opportunities for careers in engineering or the sciences.

Brainy women were not even seen as particularly desirable partners. Clever or rich men chose brides on the grounds of looks, “breeding” or both. If she did have a job, many employers would automatically fire a woman the moment she turned up with an engagement ring. So many clever, “systemising” women simply did not marry, or married late and probably had fewer children when they did.

Now everything has changed. Not only have the legal and social barriers to women entering the workplace as equals been largely dismantled, we also have the phenomenon of the desirable “alpha female”.

Fifty years ago many men were scared of smart women. Now, increasingly, alpha males want someone their equal. Fifty years ago, male airline pilots typically married stewardesses; now they marry other pilots. Doctors used to marry nurses; now they marry other doctors.

But the phenomenon of like marrying like may be having completely unexpected consequences.  

The Peter Theory of the Neuroprotective Effect of Female Hormones in Autism

Unlike Simon, I do not have a brother who is a movie star, with a Golden Globe; my brother designs car engines, but his engine did win the International Engine of the Year Award in 2013.

I always wondered why it was that kids with autism are mainly boys and when you do meet an autistic girl, she tends to be at the moderate to severely affected end of the spectrum.  Then there is Simon’s observation that alpha females produce disproportionately more kids with ASD.  Then there is the question as to why Anglo-Saxon countries (Australia, Canada, New Zealand, the United Kingdom, and the United States) but particularly the US, have a higher incidence of autism than the rest of the world; is it really just over-diagnosis?

The hormones Estrogen and Progesterone are known to be highly neuroprotective.  Testosterone may also have some neuroprotective properties, but they seem to be of a lesser extent.   While Estrogen and Progesterone are known as female hormones and Testosterone is the male hormone, both sexes have all three hormones, just in different amounts.  We learnt in an earlier post that the stress hormone Cortisol is neurotoxic.

Imagine an experiment:

On the left, you have a stressed alpha female
 (cortisol↑ testosterone↑ estrogen↓  progesterone↓)

with a male fetus (testosterone↑ estrogen↓ progesterone↓)

On the right, you have a calm beta female
 (cortisol↓ testosterone↓ estrogen↑  progesterone↑)

with a female fetus (testosterone↓  estrogen↑  progesterone↑)  

Then both subjects experience a sharp oxidative shock from the environment.

The beta female, with the female fetus, have a major neuroprotective advantage . They can generally weather the storm; only in severe cases is the neuroprotection overcome and the result is a severely autistic girl. 

The alpha female, with the male fetus, cannot weather even a moderate shock and the result is a mildly affected autistic boy.  The more rare severe shocks, produce severe autism.

The kind of insults that produce damaging oxidative shocks have been well documented by researchers like Abha Chauhan. 

Conclusion

This latest Peter Theory is hopefully flawed, after all, what do you learn about biology in Engineering School and Business School?  There should be much more talented people out there.  If it was correct, it would open up avenues in very simple preventative medicine.


P.S.   I am using a little dramatic license; Simon is actually Borat's cousin, not strictly his brother.

Central Serotonergic Hypoactivity in Autism & Degradation of Tryptophan

 

Today’s post has an impressive title and a year ago I would not have understood it, but it summarizes exactly what may be going on inside the autistic brain.  It fits into the wider puzzle of hormonal imbalances in autism that then manifest themselves into behaviours ranging from qwerky to extreme self-injury.

Human emotions and behaviours are influenced by parallel signals from the nervous system (i.e. the brain) and the endocrine system.  The two systems are interconnected and so your state of mind in controlled by hormones that you cannot directly control and the nervous system which you can learn to control.  For example, you can make yourself happy, unhappy, or depressed with the power of your mind.  You can train yourself to overcome fear.  Some people are clearly very much better at doing this than others; but the potential to do so lies within all of us, autistic or neurotypical.  This also explains why singing makes you happy and rapidly reduces cortisol, your stress hormone, as we learnt in an earlier post.

So on the one hand we need to understand any in-built hormonal disturbances in autism and then see how to best tackle them using the hormonal system and the nervous system.  This may sound like fantasy but the more you learn about it, the more plausible it becomes.

Serotonin

Most people have heard of Serotonin; it is frequently thought of as the “happy hormone”.

As we have learnt in this blog, the human body is not like any man-made invention, it seems to function in quite irrational ways.  Serotonin is found mainly in the intestines and less than 10% is in the brain (and CNS), but it is not the same serotonin.  Serotonin cannot cross the blood brain barrier.  In autism serotonin in the blood (produced in the intestines) tends to be elevated, but the level of serotonin in the brain appears to be reduced.  So there appears to be a failure in the entire serotonin system, the one for the brain and the one for the blood.

Drugs that lower brain serotonin are often used to treat the symptoms of autism.  Even Temple Grandin admits (on her own website) to being on a low dose of Prozac to control her anxiety.  In spite of a long list of side effects, many children with ASD living in the US are prescribed this serotonin lowering drug.  Prozac is a heavily prescribed antidepressant drug and is a selective serotonin reuptake inhibitor (SSRI).

Somewhat bizarrely, Prozac is linked to an increase in suicidal tendencies.  As is often the case, many drugs have secondary or tertiary modes of action; you will experience all of them.

In the language of your doctor, low brain serotonin would be called central serotonergic hypoactivity, but don’t go asking him to test it, because he cannot.  All he can do is measure the level of serotonin in the blood or urine, and probably tell you that it is slightly elevated and not to worry.

Researchers have known about this serotonin paradox in autism for many years.  To my surprise a researcher at Yale University even made a mathematical model to better understand it. 

Serotonergic paradoxes of autism replicated in a simple mathematical model

Since the early 1960s, the most consistent pathophysiological finding in autistic individuals has been their statistically elevated blood 5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic individuals have normal blood 5-HT levels, so this finding has been difficult to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood platelets and has been implicated in autism, but recent studies have found no correlation between SERT polymorphisms and autism. Finally, autism is considered a brain disorder, but studies have so far failed to find consistent serotonergic abnormalities in autistic brains. A simple mathematical model may account for these paradoxes, if one assumes that autism is associated with the failure of a molecular mechanism that both regulates 5-HT release from gut enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT receptors may play such a dual role. While the failure of such a mechanism may lead to consistent abnormalities of synaptic transmission with no alteration of brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.

 The figure below sums up what appears to be going wrong.

 

A great all-in-one overview

If you only want to read one paper on serotonin and autism, and one that is not too science heavy, the one for you is:-

A review of the serotonintransporter and prenatal cortisol in the development of autism spectrum disorders

If you have more interest, then read on …

Research on Serotonin in the Autistic Brain

A recurring problem in all brain research is the lack of physical samples.  You cannot just open up someone's head and take a brain biopsy.  Research is either carried out on the tiny number of autistic brains donated to medical research, or it is non-invasive (MRIs and EEGs etc.), or it is very indirect.  An example of this latter type is the following paper from Belgium, home of kriek, a beer made from cherries and French fries served with mayonnaise.

Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test.

"Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism."

 

Tryptophan and DHEA

Just to complicate things a little further, I now introduce you to Tryptophan and DHEA.

Tryptophan is an essential amino acid, meaning that it is essential for human life, cannot be synthesized by the organism, and therefore must be part of your diet.

Tryptophan functions as a biochemical precursor for the following compounds:

• Serotonin, synthesized via tryptophan hydroxylase. Serotonin, in turn, can be converted to melatonin (a  neurohormone).
• Niacin is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates
• Auxin (a phytohormone) when sieve tube elements undergo apoptosis tryptophan is converted to auxins

The disorders fructose malabsorption and lactose intolerance cause improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression

What you will not find on Wikipedia, is that perhaps Tryptophan is in fact also a bona fide neurotransmitter in its own right.

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

Abstract

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signaling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan. 

This paper is open access, it gets quite technical but here is a summary of the conclusion. 

Decreased tryptophan metabolism in patients with autism spectrum disorders

 

Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs

Although approximately 99% of the dietary tryptophan intake is metabolized via the kynurenine pathway, tryptophan is also the main precursor for both serotonin and melatonin

Melatonin plays a critical role in the regulation of the circadian rhythm, and anomalies of this rhythm have been associated with some of the signs in the autistic spectrum, like seizures or sleep disorders

Serotonin is a neurotransmitter involved in multiple aspects of brain functions, ranging from the regulation of mood to the control of appetite and social interactions and its production has been reported as deficient in ASD brains.

Tryptophan levels have been demonstrated to directly influence central nervous system (CNS) serotonin levels and behavior, and altered tryptophan transport has been described in fibroblasts from boys with attention deficit/hyperactivity disorder (ADHD)

Patients with ASDs, on average, are less capable of utilizing tryptophan as an energy source than controls.

Decreased tryptophan metabolism in patients with ASDs may alter metabolic pathways involved in the regulation of the early stages of brain development (first month of gestation), mitochondrial homeostasis and immune system activity in the brain.

Disruption of such pathways can primarily be caused either by insufficient serotonin production by placental cells, mitochondrial dysfunction and/or impaired balance between quinolinic and kynurenic acid in fetal cells. The combined effects of these events could lead to abnormal organization of neurons , particularly in specific brain regions, determining the imbalance between the short- and long-term circuitry that has been considered to be one of the fundamentals of the ASD neuropathology

Even though the ideal target tissue, brain, could not be investigated, our observation of decreased tryptophan metabolism in cells from patients with ASDs may provide a unifying model that could help explain the genetic heterogeneity of ASDs.

Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD⁺, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.

DHEA

DHEA  (didehydroepiandrosterone) It is the most abundant circulating steroid in humans, importantly for us to know it is also produced in the brain.  It has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface and acting as a neurosteroid.

Faulty serotonin--DHEA interactions in autism: results of the5-hydroxytryptophan challenge test. 

Abstract

BACKGROUND:

Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients.

METHODS:

Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls.

RESULTS:

The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic) versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic potential occurs in autism.

CONCLUSIONS:

It is concluded that disequilibrium in the peripheral and central turnover of serotonin and an increased neurotoxic capacity by glucocorticoids are important pathways in autism.

 

Mice Studies

For the mice lovers amongst you, they also get their vitamin P (Prozac).

Serotonin Defects Identified in "Autistic" Mice

 

Serotonin modulators mitigate some BTBR behaviors

The researchers tested the effects of acute doses of fluoxetine (Prozac) (an SERT blocker), risperidone (a 5-HT_2A receptor antagonist), and buspirone (a partial 5-HT_1A receptor agonist) on social and repetitive behaviors of BTBR mice. These three compounds regulate serotonin activity and have inconsistent, limited, and sometimes harmful effects in rodent models of and people with autism. Only buspirone and fluoxetine were found to make BTBR mice significantly more social: treated mice spend proportionally more time socializing with a strange mouse than do saline-treated controls. Interestingly, BTBR mice treated with either buspirone or fluoxetine show a reduced interest in social novelty: when introduced to a second stranger mouse, they do not show a preference for either stranger. In contrast, the saline-treated controls spend more time investigating the newer mouse. Compared to either buspirone- or fluoxetine-treated mice and saline-treated controls, Risperidone-treated mice spend less time investigating strange mice and novel surroundings.

Regardless of treatment, BTBR mice spend comparable amounts of time burying marbles (an index of repetitive behavior). However, eliminating from the analysis one saline-treated control that did not bury any marbles suggests that risperidone-treated mice bury significantly fewer marbles than the saline-treated controls.

In summary, Daws and her team concluded that the autism-like behaviors of BTBR mice are likely due in part to an altered hippocampal SERT serotonin transporter and/or an altered 5-HT_1A serotonin receptor. These findings may lead to the identification of additional therapeutic targets for treating human autism.

 

Conclusion

There was a lot of science in this post and it was clear that the mechanisms involved are only very partially understood by researchers.

It is clear that interventions increasing central (brain) serotonin levels are likely to reduce autistic behaviours.  Prozac was mentioned, but there is a much wider class of drugs called serenic, many of which could potentially be helpful.  As mentioned earlier, the big problem with most of the drugs created for psychiatrists is side effects.  Autism is supposed to be very common, but you would not think so by looking at way new drugs are developed.  As a result, the drugs currently used in ASD and the majority of those in the pipeline are ones developed for other conditions (depression, bi-polar, psychosis , anxiety, ADHD, schizophrenia, Alzheimer’s etc.) many of which share some similar characteristics, but are essentially different conditions, with the exception of ADHD.  It is akin to trying to fix your Ford car with a parts bin filled with Toyota components; it is possible, but not a wise idea.

In my opinion, all the hormone dysfunctions in autism can eventually be traced back to damage caused by oxidative stress and neuroinflammation.  The brain has just adjusted to find a new homeostasis, which happens to be an autistic one.  The list of metabolic disturbances in autism is long and getting longer; but they are just consequences.  I very much doubt it is ever going to be possible to go hormone by hormone, neurotransmitter by neurotransmitter “correcting” them.   I think the best solution is to go further back up the chain and look at how hormones and neurotransmitters themselves are jointly regulated.  I do not believe anyone fully understands the molecular basis on which this is carried out, but as I have pointed out earlier in this blog, you can get the right answer for the wrong reasons and also without showing your workings.  As long as it works, perhaps understanding why does not matter.  A much less intellectual approach might indeed prove effective.

I will continue with my problem solving, but less intellectual, approach and see where it leads.

 
P.S.
 
Just to show how all the hormones are interrelated, I added the paper below from Japan.  They investigate the relationship between Oxytocin and Serotonin:

Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice

"It is thus possible that oxytocin modulates not only anxiety-related behavior but also social behavior via serotoninergic transmission. These observations may provide new insights into psychiatric disorders associated with disruptions in social and emotional behavior, including autism, anxiety disorders, and depression."