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Thursday, 23 November 2017

Under-expression (Haploinsufficiency) of ARID1B in Autism and Corpus Callosum Abnormalities


People keep telling me that my blog is too complicated; compared to the literature it really is not. If your child has a disabling condition you really should be willing to invest all the time needed to learn about it, rather than be a passive bystander.
I think you can investigate even complex sounding genetic disorders without being an expert, which is what happens in today’s post.  

Are there 20,000 types of jeans?

As readers may recall, humans only have about 20,000 genes, far less than originally was thought. Each gene provides the instructions to make one thing, usually a protein.
For the great majority of genes we have two copies, one from Mum and one from Dad. Mitochondrial genes all come from Mum.
These genes are stored on chromosomes (like recipe books).
For 22 of these recipe books you have two copies, so if one page got damaged at least you have an undamaged version from the other book.
The 23rd pair of books is special because while females have two copies, males do not. This is the X chromosome and if a male has a problem on any page in this little book, he has a big problem, while his sister has less of a problem, because she has a spare copy. The male has a Y chromosome in place of a second copy of X. 
Examples of problems on the X chromosome:-

·        The MECP2 gene is on the X chromosome and when there is one working copy and one mutated version you have Rett syndrome and you must be female. If you were male with one mutated version you cannot survive.

·        In Fragile X syndrome a problem with the FMR1 gene means not enough not enough fragile X mental retardation protein (FMRP), which is required for normal development of the connection between neurons. Females would normally have a clean spare copy of the FMR1 gene and so show much less severe symptoms that a male with Fragile X.

Problems on chromosomes 1 to 22:-

If you have a problem in the first 22 chromosomes (recipe books), boys and girls are equal. If one page got damaged you can always look up the recipe in the other book.
In case one gene got mutated but the other copy is fine, things can work out just fine, in which case it is called haplosufficiency. You get to make enough of that protein.
In some cases you really need to use that recipe a lot; that particular protein is in big demand. One copy of that gene just is not enough. This is called  haploinsufficiency.
In most cases when the gene has a problem, it just fails to produce the intended protein. In some cases it actually produces a mutated protein, which can be worse than no protein. 

Pitt Hopkins

In Pitt Hopkins Syndrome there is a problem on chromosome 18, where you find the TCF4 gene. Not enough expression of TCF4 means not enough Transcription Factor 4;  this is an example of haploinsufficiency.
Now the reason why these rare conditions are important to many other people is that they not only affect people who happened to have a random mutation and hence a severe deficit of the protein; moderately reduced transcription of this gene, for any reason, can also result in troubling symptoms.
So in the case of the Pitt Hopkins and the gene TCF4, as was pointed out to me recently, reduced expression is a feature of some MR/ID and indeed schizophrenia. 


Instead of just a tiny number of people with Pitt Hopkins, you can see that upregulating TCF4 expression could help a lot of people.
It appears that people with Pitt Hopkins have a “clean copy” of TCF4, so it is just a case of making it work a little harder. There are ways being researched to achieve just that.
I suspect people with schizophrenia have two “clean copies” of TCF4, but for some reason have a deficiency of the protein encoded by it.
In the above paper it was shown that Protein Kinase A (PKA) plays a key role in regulating what your TCF4 gene is producing.
We have come across PKA before in this blog and we know that in regressive autism there can be a deficit of PKA. There is also PKB and PKC. All three are very important, but complicated. 


Without going into all the details you can see that if someone with Pitt Hopkins has a lack of PKA, like those with regressive autism, then he will struggle to make the most of his good copy of the gene TCF4.

It all gets very complicated, but PKA is controlled by something called cAMP. In turn cAMP is controlled by PDE. PDE4 is known to be disturbed in the brains of some people with autism.
It appears that you can activate PKA with a PDE4 inhibitor. The long established Japanese asthma drug Ibudilast is such a PDE4 inhibitor. At least one reader of this blog uses Ibudilast long term.


PDE4 inhibitors have been explored to treat various neurological conditions like schizophrenia.

So logically if you feed a PDE4 inhibitor to a Pitt Hopkins mouse, you might expect something good to happen. There now is such a mouse model.

I think I could keep that mouse quite busy. 
The point being you do not have to figure things out 100%, before starting to see what you have in your drug library might be truly beneficial.  
Some of the things in the drug library are actually in the kitchen cupboard, as we have already seen. 

Protein Kinase A
Protein kinase A (PKA) is something that is both complicated and important.
The effects of PKA activation vary with cell type.
PKA has always been considered important in formation of a memory.  Formation of a normal memory is highly sensitive to PKA levels; too much is bad and too little is bad.

ARID1B in Autism and Corpus Callosum Abnormalities
I don’t think anyone has set up a research foundation for agenesis of the Corpus Callosum (ACC), perhaps they should. 
There was a post on this a while back, prompted by meeting someone whose son has this condition. 

The Corpus Callosum is just a fancy name for what joins the two sides of the brain together. Agenesis of the Corpus Callosum (ACC) is what they call it when there is a complete or partial absence of the corpus callosum.

ACC is we are told a very rare condition, but clearly smaller corpus callosum variations are a key part of some autism. 
For example, in Pitt Hopkins a small corpus callosum is typical.
An estimated 7 percent of children with autism and macrocephaly (big heads) carry a PTEN mutation. This is associated with an enlarged corpus callosum. 
PTEN is an autism gene, but it is more usually thought of as a tumor suppressor, making it a cancer gene. In older people, losing PTEN appears to be often a first step to developing cancer; up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis  (https://www.ncbi.nlm.nih.gov/pubmed/16079851). 

PTEN is interesting because too little can allow cancer to develop, but too much may eventually result in type 2 diabetes. So, as always, it is a balance. 


Evidently from the comments in this blog, regarding tumors/cancers, people with autism are likely shifted towards the direction of lacking tumor suppressing proteins. The exception would be those born very small, or with small heads. 

ARID1B gene
ARID1B is another tumor suppressing gene, like PTEN, and like PTEN it is also an autism gene.
What I found interesting was the link between ARID1B and corpus callosum anomalies. 

ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability  



Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30–50% of the cases, but the underlying genetic cause remains unknown in the majority of cases.
Additional functional studies including a systematic search for ARID1B target genes may show how haploinsufficiency of ARID1B predispose to CC defects and to an array of cognitive defects, including severe speech defects

Several readers of this blog have highlighted a recent study:-  


We showed that cognitive and social deficits induced by an Arid1b mutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies." 

The full study:-


Clonazepam also reversed the reduced time spent in the center and reduced moving distance displayed by Arid1b-mutant mice in the open field test (Fig. 7c,d and Supplementary Fig. 14c). However, depression measures, using the forced swim test and the tail suspension test, showed no reversible effect of clonazepam in Arid1b+/− mice compared with controls (Fig. 7e,f). Our results show that clonazepam rescues impaired recognition, social memory, and elevated anxiety in Arid1b+/− mice. 
Our mouse model effectively mirrors the behavioral characteristics of intellectual disability and ASD. Arid1b+/− and Arid1bconditional-knockout mice displayed impaired spatial learning, recognition memory, and reference memory. Open field and social behavior tests also revealed decreased social interaction in the mice. Mice with mutations in genes encoding Smarca2 and Actl6b, other subunits of the BAF complex, have severe defects in social interaction and long-term memory35. Thus, this chromatin remodeling complex may provide a cellular and molecular platform for normal intellectual and social behavior. In addition, Arid1b+/− mice showed heightened levels of anxiety- and depression-related behaviors, which are common symptoms of ASD36. 
For people with intellectual disability, the prevalence of anxiety disorders has likewise been shown to be much higher. This may be due to reduced cognitive function and increased vulnerability to environmental demands. Communication difficulties may also make it more difficult for people with cognitive disabilities to deal with anxiety or fear. ARID1B haploinsufficiency may be responsible for multiple facets of characteristic ASD behaviors. Other isoforms of Arid1b that are not affected by the Arid1b mutation could exist in the mouse line. Additionally, it is possible that the genetic background for the mouse line may impact the effect of Arid1b haploinsufficiency. Thus it is important to consider allele specificity, genetic backgrounds, and knockout strategies for comparing phenotypes of other Arid1bhaploinsufficiency models.  
GABA allosteric modulators, including clonazepam, a benzodiazepine, have been used to treat seizures and anxiety. We found that clonazepam injection rescued deficits in object and social recognition and anxiety in Arid1b+/− mice. These results suggest that treatment with a benzodiazepine could be a potential pharmacological intervention for symptoms of ASD. Furthermore, our results suggest that pharmacological manipulation of GABA signaling is a potential treatment strategy for cognitive and social dysfunctions in ASD- or intellectual disability-associated disorders due to mutations in chromatin remodeling genes.  

ACC Research Foundation
If there actually was an ACC Research Foundation, they could explore whether clonazepam was therapeutic in children who have Arid1b haploinsufficiency.
While they are at it, they might want to look into Hereditary Motor and Sensory Neuropathy with agenesis of the corpus callosum (HMSN/ACC), this is caused by mutations in the potassium-chloride co-transporter 3 (SLC12A6/KCC3) gene. This I stumbled upon a long time ago, when trying to upregulate KCC2, which causes elevated intracellular chloride in many people with autism and likely many with Down Syndrome.

KCC2 is usually associated with neuropathic pain and now we see that so is KCC3. Odd reaction to pain is a well known feature of autism. The rather ill-defined condition of fibromyalgia seems common in female relatives of those with autism and I do not think this is just a coincidence. 
The interesting thing is that the research shows you can potentially upregulate KCC3 with curcumin. 

HMSN/ACC is a severe and progressive neurodegenerative disease that exhibits an early onset of symptoms. Signs of HMSN/ACC, such as hypotonia and delays in motor development skills, are noticed before 1 year of age. However, the motor abilities of patients progress slowly to 4–6 years of age, and these children are able to stand and walk with some help. This is followed by a motor deterioration that generally renders affected subjects wheelchair-dependent by adolescence. 
Accordingly, we found that curcumin relieved the ER retention of dimerized R207C in mammalian cultured cells. A diet enriched in curcumin may therefore be beneficial for the relief or delay of some of the HMSN/ACC symptoms in patients bearing the R207C mutation, including the Turkish patient described in this study (as patient has not yet reached puberty).

KCC3 defects also cause the very similar Andermann syndrome also known as agenesis of corpus callosum with neuronopathy (ACCPN).
KCC3 defects are associated with epilepsy.
My question was can you have KCC3 under-expression with partial ACC, epilepsy but no peripheral neuropathy? If this was likely, then upregulating KCC3 with curcumin might help.
The gene for KCC3 is located at chromosome 15q14. Based on my “logic of associations”, if you have ACC and epilepsy you should consider KCC3 under-expression.
I did suggest to my former classmate whose son has partial ACC and epilepsy, but no neuropathy, that it might be worth trying some curcumin. Since his son is already on anti-epileptic drugs (AEDs) my suggested effect to look for was improved cognitive function.
6 months later it does indeed, apparently, improve cognitive function.  Of course this does not establish that upregulating KCC3 had anything to do with it. It is nonetheless a nice story and another parent has realized that you can change things for the better, in spite of what neurology currently says. 
The question now is can you have both ARID1B under-expression and KCC3 under-expression, in which case you would add some clonazepam, based on the latest research. At this point you should of course go and talk to your neurologist, rather than read my blog and that was my recommendation. 


We describe a patient who presented at our epilepsy-monitoring unit with myoclonic jerks, and was diagnosed with juvenile myoclonic epilepsy (JME). Imaging of his brain revealed partial agenesis of the corpus callosum (ACC). We discuss the known genetic basis of both JME and ACC, as well as the role of the corpus callosum (CC) in primary generalized epilepsy. Both JME and ACC are associated with gene loci on chromosome 15q14. Structural brain abnormalities other than ACC, such as atrophy of the corpus callosum have been reported in patients with JME. ACC has been associated with seizures, suggesting an anti-epileptogenic role of the corpus callosum

Conclusion

If you have a biological diagnosis you are one big step closer to finding a therapy. Even if you have a diagnosis like partial Agenesis of the Corpus Callosum (ACC), you can go one step further and ask why. You have a 50% chance of being able to find out a specific gene that is the cause. If you know with certainty which gene is the originator of the problem, you know a lot.  I think you are then two big steps closer to a therapy.
In the case of Rett Syndrome, a really good website is run by their research foundation (Rett Syndrome Research Trust). They look like they mean business. 


If you look at the above site you might be left wondering why the much larger and better financed autism organizations look so amateur by comparison.  The big difference is that Rett Syndrome is a biological diagnosis and autism is not. In many ways calling autism a spectrum is not helpful, as the originators of the ASD concept are beginning to realize.  The precise biological dysfunctions are what matter and lumping together hundreds of miscellaneous brain dysfunctions into a pile labelled ASD may not be so clever, in fact I would call it primitive.









45 comments:

  1. Hi Peter / folks, any insights on rescuing partial NRXN1 deletion (causing hyperactivity, autistic features, sleep issues)?

    ReplyDelete
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    1. Your gene/protein neurexin NRXN1 has a close relationship with neuroligin NLGN1.

      Neurexims and neuroligins both affect the excitatory/inhibitors balance that is at the core of autism. But there are different types of E/I imbalance.

      The balance between NLGN1 and NLGN2 appears to determines one type of E/I balance.

      You need to read up about NLGN1 as well as NRXN1.

      Does anyone in the family have insulin-dependent diabetes? Or had gestational diabetes? NRXN1 has an effect on beta cells that make insulin.

      Does your son have typical IQ? Lack of NRXN1 would have a negative effect on cognition.

      Folic acid appears to increase NLGN1 expression:-

      https://www.ucalgary.ca/usrp/files/usrp/vogelaar-michelle2.pdf

      Neuroligin (NLGN) 1 expression is increased in cultures reared in the presence of 5M4Hfolate and an upstream metabolite of folic acid, 4Hfolate.

      Expression levels of NLGN1 may be altered by changes in epigenetic regulation of the gene

      Increase in NLGN1 expression is associated with an increase in excitatory synapses in neuronal networks

      Modifying his E/I imbalance might reduce hyperactivity and indeed sleep problems, you need to shift it away from E towards I.

      My son’s E/I imbalance responds to bumetanide and low dose clonazepam. Which affect GABAa. Some people’s E/I imbalance responds to modulating NMDA receptors.

      Neuroligin2 (NLGN2) does affect GABAa and KCC2 expression and if that was affected that would suggest bumetanide as being possibly helpful.

      Delete
    2. Thank you so much for your answer, Peter. I need to digest this carefully.

      No insulin issues in family. IQ not measured, but the boy (yes, you assumed right) is clever. I would love to try bumetadine, but I have to persuade the physician for that trial. Targeting NMDA receptors seems interesting as well.

      Delete
    3. Ask your physician also about calcium folinate (Leucoverin). This is like super strength folic acid and the Canadian research suggests it might "hyper-methylate" the NLGN1 gene which means epigenetically modify it to increase its expression to make more NLGN1, which should help shift E/I balance towards I.

      Since your son has normal IQ, you do not have a severe case, so folic acid might be all you need.

      Delete
    4. Thanks for the advice.

      I had some troubles to understand the poster you linked. So, is it that methyl folate (as well as Leucoverin) should increase the expression of NLGN1 gene and help shifting E/I balance towards inhibitory (=less hyperactive), even though Leucoverin is more potent?

      Delete
    5. Yes, I think all folates might indeed help. Some may work better than others. Leucoverin contains a very high dose, most OTC supplements have a tiny dose.

      Delete
    6. Hey Peter, even the small dose of methylfolate (200-400mcg) helps and sometimes normalizes the behaviour. The effect lasts 1-2 days, but maximum of one week, if given regularly. After that, a really bad mood and hyper follows. Supplementing with b12 does not help. I can't figure out the problem, but I think it may be partly related to histamine. He has allergies and also bad responses on NAC, b3, biogaia probiotics, for example.

      Any insights on longterm use of folate and how to overcome the side effects?

      Thank you for your comments.

      Delete
    7. I know some people take taurine to avoid some folate side effects. I am not sure why this would help.

      Many people use certain supplements intermittently to avoid them losing their effect, or giving side effects. This is normally a problem caused by the body's own feed back loops that resist whatever change you are trying to make.

      Delete
    8. Thanks for the tip!

      Delete
  2. Wonder if those who benefit from PDE4-i/cAMP/PKA would also benefit from CILTEP (artichoke extract, forskolin and a bunch of other stuff in it)

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  3. A new paper shows how R-Ras signaling (which Peter has covered before) is integral to angiogenesis:

    Press Release:

    https://www.sciencedaily.com/releases/2017/11/171123094343.htm

    Paper:

    https://www.nature.com/articles/s41467-017-01865-x


    This is interesting in that R-Ras is implicated in a study linking cancer and autism to SHANK3, that I believe Peter covered in a previous blog post:

    Press Release:

    https://www.sciencedaily.com/releases/2017/03/170309120632.htm

    Paper:

    https://www.nature.com/articles/ncb3487

    So one can generalize here that either having too much R-Ras or too little is going to lead to vascular problems and vascular problems seem to be a common theme with autism and perhaps NO boosting substances have a positive effect in some people with autism for this very reason, especially since errors in R-Ras may cause blood vessels to not fully function, in spite of whatever VEGF does initially to stimulate angiogenesis.

    Strangely, I did a quick search for "angiogram autism" and found nothing and wonder if anyone has actually done a study to look at the physical cerebral vasculature in autism, rather than just through indirect methods like fMRI.

    ReplyDelete
    Replies
    1. Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.

      You have the Ras superfamily and then within it the Ras subfamily. There are 33 members of the Ras subfamily which includes R-Ras.

      Mutations of Ras genes and others along the RAS pathway are called RASopathies.

      Several RASopathies are associated with MR/ID and autism, such as Neurofibromatosis type I (NF-1), which causes benign and malignant nervous system tumors, but they are accompanied by autism/MR/ID.

      The NF-1 gene is a negative regulator of the Ras signaling pathway. Without enough expression of this gene, there is too much Ras signaling. The result is tumors anywhere in the body and brain damage (autism).

      Delete
  4. Thank you, thank you Peter for this post! I totally agree with that first paragraph.

    My daughter just got her preliminary genetic results, and indeed, it looks like she has a very rare monogenic syndrome. Oh my.

    /Ling

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  5. Hi Peter,
    I was able to procure Clonazepam tables.How do I grind it?It was 2.5 mg.It is not easy to get.Could you please let me know
    Thanks
    SB

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    Replies
    1. SB, in my case it is a 2mg tablet that has a marks on it to help you split it into quarters. I put one quarter in 100ml of water in a small glass bottle in the fridge. It gradually dissolves, the I use a hand held frappe mixer that fits inside the bottle to give a thorough mix. Then I have 0.005 mg/ml. I use a syringe the withdraw 6ml. You need to mix/shake well each time, because the tablet does not dissolve well, it just forms a suspension.

      Delete
  6. Piracetam apparantly works through improving the corpus callosum.

    On a side note back to what tyler was saying about the pde4-i's.
    I tried CILTEP yesterday and it is amazing honestly (900mg artichoke extract which is a source of luteolin, 5mg forskolin and 750mg tyrosine) gives very good clarity and seems to give me a sense of reward for small achievements (which I normally dont seem to get, this stood out the most), anyway this was a sporadic decision and Ive written it in my log.

    Today im back to inositol and cordyceps again as I want to see in my upcoming bloodtests how good cordyceps is at lowering urea in autism (if it drops my urea levels even more which I hope).
    Would be great if this would reduce urea in those with autism, after all bloodtests wont lie and others who visit this blog might benefit from this aswell.

    Back to CILTEP, it increases PKA/cAMP aswell as cordyceps.
    PKA/cAMP/MAPK p32 is needed for SERT expression (increasing SERT lowers serotonin which is often high in autism), cAMP/PKA/MAPK is also necesarry for the mu-opioid receptors.

    Copy paste from my post on reddit with regards to mu-opioid receptor knockout model for autism and the search for mGLUR4 agonists:

    https://www.reddit.com/r/Nootropics/comments/7fgmoz/social_hedonic_capacity_is_associated_with_the/

    ReplyDelete
    Replies
    1. L-Tyrosine is of course a precursor to dopamine so it is not a surprise it makes you feel good or even alert. The military has used it for maintaining alertness for extended missions in addition to other stimulants. For anyone with hyperactive dopamine issues which is likely most people with autism, L-Tyrosine is a bad idea.

      Delete
    2. Tyler,

      Im speaking for myself (Aspergers) it is pretty obvious I need dopamine, also dopamine isnt all stimulatory, it depends on which receptors you hit, for example pramipexole (a dopamine agonist for parkinsons) can cause people to fall asleep, its mainly norepiphedrine and adrenalin that peps people up.

      One of the reasons why I never understood antipsychotic medication for alot of types of autism is also the side effects, obesity, tardive dyskinesia just to name a few, which are horrible in their own realm, not to mention these side effects can make someone worse both physically and mentally.

      This just shows there isnt a 1 size fits all pill for all the subtypes of autism, it may require drugs at the oposite end to target certain subtypes.

      Besides, since we are on the topic of PDE4-inhibitors, they have also been investigated in use for anhedonia.

      Phosphodiesterase 4 inhibitors enhance sexual pleasure-seeking activity in rodents
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065502/

      Im sure this would translate to humans aswell, just one example.

      You cant expect to take a pill and have all positives without zero side effects, thats just not going to happen.

      Delete
    3. Well plain old dopamine which comes from L-Tyrosine via L-Tyrosine -> L-DOPA -> Dopamine is facilitative and combats fatigue. The drug you speak of primarily works on D2 and D3 receptors, not D1 receptors which is stimulated by dopamine (as well as D2 receptors).

      Dopamine itself is about as natural as stuff gets but it is non-selective which makes dumping large amounts of it into the extracellular space to be about as useful as SSRI's in terms of their negative side effects.

      Also, people with more severe cases of autism sometimes will take beta-blockers to deal with chronically elevated catecholamine levels in the brain as well as the periphery, so I just don't see any evidence where supplemental dopamine (not drugs working on specific receptors) is going to help autism symptoms for anyone with autism.

      The only time I have heard of dopamine being used for autism is in this study which is quite old:

      https://www.researchgate.net/publication/226241817_Effects_of_L-Dopa_in_autism

      In effect, the idea back then was because serotonin was found to be very high in subjects with autism, that if you exploit the antagonistic effects dopamine has with serotonin, that you will lower serotonin levels which this study showed was successful, though there were no improvements in actual autism symptoms. Also, the side effects of long-term use of L-DOPA are pretty clear from Parkinson's research.

      All of that being said while L-Tyrosine will raise dopamine levels somewhat for an extended period of time if taken in free form, the conversion of L-Tyrosine to dopamine is still rate limited by its conversion to L-DOPA and the AADC enzyme. On top of that, you find L-Phenylalanine and L-Tyrosine in abundant amounts in many foods, including meat and dairy and in terms of plants I believe peanuts are an abundant source. 750mg (assuming it is even absorbed as well as free form L-Tyrosine) is not a huge amount of L-Tyrosine anyways.

      Delete
  7. Forgot to add, my clostridicum butyricum has arrived also, though have not yet started it, will do so after I have my bloodwork.

    https://ibb.co/gyqBCm

    Peter why is it that everything that activates PKA/PKC/IP3 positively influences me, my knowledge is not good enough for this, to name a few: inositol, phosphatidic acid, phosphatidylserine, ciltep, cordyceps and a bunch more(they all activate either PKA, PKC or IP3)

    Phosphatidic acid directly activates endothelial cell protein kinase C.
    https://www.ncbi.nlm.nih.gov/pubmed/8447819

    Counter-regulatory effects of phosphatidic acid on protein kinase C activity in the presence of calcium and diolein.
    http://europepmc.org/abstract/med/2393403

    "Phosphatidic acid can replace phosphatidylserine in the activation of protein kinase C. However, in the presence of diolein, the addition of Ca2+ results in the inhibition of the enzyme. This phenomenon could lead to a negative feedback regulation of protein kinase C activity as a result of stimulation of the cycling of phosphatidylinositol."

    Effects of Soy Lecithin Phosphatidic Acid and Phosphatidylserine Complex (PAS) on the Endocrine and Psychological Responses to Mental Stress
    http://www.tandfonline.com/doi/abs/10.1080/10253890410001728379

    A soy-based phosphatidylserine/ phosphatidic acid complex (PAS) normalizes the stress reactivity of hypothalamus-pituitary-adrenal-axis in chronically stressed male subjects: a randomized, placebo-controlled study
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237891/pdf/1476-511X-13-121.pdf

    A soy-based phosphatidylserine/ phosphatidic acid complex (PAS) normalizes the stress reactivity of hypothalamus-pituitary-adrenal-axis in chronically stressed male subjects: a randomized, placebo-controlled study
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237891/pdf/1476-511X-13-121.pdf

    "Results Serum PS peaked 90 min after ingestion, returning to baseline after 180 min. In the elderly, PS+PA [per protocol (PP) n = 31], unlike placebo (PP n = 26), SIGNIFICANTLY IMPROVED MEMORY AND PREVENTED “WINTER BLUES” in a pre–post comparison. In the patients with AD, daily functioning (i.e., 7 activities of daily living) under PS+PA (PP n = 53) remained unchanged, but declined from 5.62 to 4.90 under placebo (PP n = 39; P = 0.035), with significant group difference (P = 0.021). The PS+PA group had 3.8% deterioration and 90.6% stability in daily functioning, compared to 17.9% and 79.5% under placebo, respectively (P = 0.066)."

    Protective action of phosphatidylserine on stress-induced behavioral and autonomic changes in aged rats.
    https://www.ncbi.nlm.nih.gov/pubmed/1770977

    Once again alcohol also affects PKA/PKC/GABA-A(neurosteroids)/NMDA:

    https://en.wikipedia.org/wiki/Effects_of_alcohol_on_memory

    "Furthermore, acute alcohol intake promotes GABAergic neurotransmission via presynaptic release of GABA, dephosphorylation of GABAA receptors (increasing GABA sensitivity), and elevation of endogenous GABAergic neuroactive steroids.[11] Protein kinase C (PKC) has been implicated in differentially modulating the response of the GABAA receptor to alcohol, with effects depending on the PKC isozyme.[12] Alcohol effects have also implicated protein kinase A in affecting GABAA receptor function, such as promoting sensitivity.[13] Enhancement of GABAergic transmission due to alcohol consumption can also be brought about by neuroactive steroids, such as allopregnanolone, which act as GABAA receptor agonists.[11][14]"

    Seems alcohol temporarily blocks LTP, causing a compensatory increase in LTP during the hangover? It is well known that the NMDAr2b subunit is increased during hangover, including in the amygdala.

    Now I have looked into magnesium-l-threonate before and chronic use of this increases the NR2B subunit in the frontal cortex but not in the amygdala.

    ReplyDelete
    Replies
    1. Aspie1983 - PKA, PKB (Akt) and PKC play important roles in many biological processes, relevant to autism.

      IP3 appears to be particularly important in autism and has been covered before in this blog.

      The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R
      https://epiphanyasd.blogspot.com/2017/04/the-excitatoryinhibitory-imbalance.html

      Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

      https://epiphanyasd.blogspot.com/2015/10/is-dysregulated-ip3r-calcium-signaling.html

      Delete
    2. Aspie, did you try Phosphatidyl Serine (PS) ? This is widely sold as cognitive enhancer and as you point out really should activate PKC.

      The calcium released by IP3 works in complex way involving phospholipase C, together with DAG (diacylglycerol), to activate PKC.

      PS might well be helpful.

      Delete
    3. Hi Peter,

      Yes I have it in my house though not using currently.

      https://ibb.co/miTq56

      Have had quite a good effect of it in the past, especially since I seem to have problems forgetting where I put my keys and such, it tremendously helps with that.

      Its also very good for increasing parasympathetic tone.


      Could DAG activation by peanutbutter also explain some of my (and mainly adhd kids from what ive read on other forums?) cravings?

      https://en.wikipedia.org/wiki/Diglyceride

      "Food additive:
      Diglycerides, generally in a mix with monoglycerides (E471), are common food additives largely used as emulsifiers. The values given in the nutritional labels for total fat, saturated fat, and trans fat do not include those present in mono- and diglycerides[citation needed]. They often are included in bakery products, beverages, ice cream, --> PEANUT BUTTER <--, chewing gum, shortening, whipped toppings, margarine, confections, and candies"

      Orange juice is something else I could never stop drinking and still today if I get some fresh OJ like a liter I would drink the entire bottle at once lol, one of the reasons I stopped buying them as theres also too much sugar in it.
      Orange juice is also one of the top sources of inositol (aswell as peanuts) and vitamin c, I guess you could call orangje juice and oxytocic drink in that way.

      Back to your article and PDE4-inhibition and PKA/cAMP activation, it seems the "creator" of the CILTEP stack who has a blog aswell notes that the following have potential aswell:

      Fisetin:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1637622/

      "These data are consistent with earlier results obtained using PC12 cells which showed that fisetin treatment does not result in the activation of the cAMP target protein kinase A (3) and indicated that FISETIN ACTIVATES CREB THROUGH A MECHANISM THAT IS DISTINCT FROM THAT OF ROLIPRAM."

      Now I know I have been somewhat flamed in the past about the possible dangers of chinese skullcap in some papers (mainly on the liver).

      However it seems this herb has quite alot of unique properties:

      Long termp potentiation, prolyl endopeptidase inhibitor (increases oxytocin half-life), gaba a2 and a3 subunit PAM

      Baicalin improves chronic corticosterone-induced learning and memory deficits via the enhancement of impaired hippocampal brain-derived neurotrophic factor and cAMP response element-binding protein expression in the rat.
      https://www.ncbi.nlm.nih.gov/pubmed/23749289

      GABA A receptor subtype selectivity underlying selective anxiolytic effect of baicalin.
      https://www.ncbi.nlm.nih.gov/pubmed/18723037

      " In contrast to the classical BZ diazepam, baicalin showed significant preference for alpha2- and alpha3-containing subtypes compared to alpha1- and alpha5-containing subtypes in whole-cell patch clamp studies (P < 0.01). Its subtype selectivity suggested that baicalin exerted its in vivo anxiolytic-like effect mainly through the -->> alpha2- and alpha3-containing subtypes. <<--"

      https://en.wikipedia.org/wiki/GABRA2

      "GABRA2 mediates neural activity necessary for information processing in inter-neurons.[7] GABRA2 participates in transporting Cl− ions into the membrane"

      "GABRA2 is associated with reward behavior when it activates the insula.[9] The insula is part of the cerebral cortex responsible for emotions."

      "Since GABRA 2 mediates anxiolytic activity, it is a key receptor for emotional control."

      https://en.wikipedia.org/wiki/GABRA3

      "Recent research has produced several ligands that are moderately selective for GABAA receptors containing the α3 subunit. Subtype-selective agonists for α3 produce anxiolytic and mild sedative effects, but without causing amnesia or ataxia, which could make them superior to currently marketed drugs"

      "upregulation of KCC2 cotransporter."

      Pure baicalin is also available on the internet, liftmode sells it but shipping to where I live is insanely expensive so I did not order it in the past.

      Delete
    4. Aspie, do you happen to have the reference for the statement "Now I have looked into magnesium-l-threonate before and chronic use of this increases the NR2B subunit in the frontal cortex but not in the amygdala."?
      I would love to read that!

      /Ling

      Delete
    5. I found the reference myself, here:
      https://www.ncbi.nlm.nih.gov/pubmed/25152202

      /Ling

      Delete
  8. Peter, regarding azithromycin safety, iam not completley sure to try it, do you know if it may have potencial cardiac risk? I have it at home but don´t know what to do.I was planning to give him 250 mg every other day. Valentina

    ReplyDelete
    Replies
    1. Valentina, azithromycin is the subject of the next post which will appear in a couple of days.

      I think you have to ask your doctor relative about drug safety. Giving the drug every other day is a clever idea and this was also done in a case I am familiar with.

      Delete
    2. Peter, it seems that excess risk is negligible:

      https://www.medscape.com/viewarticle/878692

      Valentina

      Delete
  9. Came a across an interesting find with regards to practical spermidine supplementation in children (scroll down to bottom of page):

    http://www.longecity.org/forum/topic/97734-spermidine-longevity-source-from-japan-yogurt-starter-culture/#entry830313

    On essence there is a probiotic strain that generates a lot of spermidine and ironically is sold as.a children's probiotic. Aside from this method, the next most practical option I know of is to eat at least a cup of wheat germ a day to increase the levels of spermidine in the body to promote longevity effects.

    Of course the interest here is for therapeutic purposes with respect to autism and polyamines and in particular spermidine are important in maintaining healthy chromatin structure in cells, a feature which seems to be compromised in autism (sorry on phone so hard to dig up links to cite).

    Polyamines are also important in regulating the activity of neurons.

    I have to look more into this product to guess what amounts could be good to increase spermidine levels to a useful therapeutic level, but fermenting it should be a viable option as well if the yield needs to be increased.

    ReplyDelete
  10. Hi Peter,
    My adult son has been taking NAC for about 2 years. it significantly reduced his rages. I have tried never to be without it. He takes Jarrow extended release 600 mg caps. He was taking up to 8 daily.
    This week for the first time in the 2 years, we ran out and the new batch has not yet arrived.
    Is it coincident that my son seems happy, quick to smile, even more compliant and attentive than I have seen him in a long time? (His mood has deteriorated over the past several months) I can't attribute this upbeat and slightly more engaged state to anything different except that he is not taking NAC this week.
    Could there be some correlation?
    Thanks
    Nancy

    ReplyDelete
    Replies
    1. The trajectory of autism symptoms can change quite a bit as a child gets older as well as morphologically what goes on in the brain as there seems to be an excess of neurons in early childhood and then by adulthood you seem to get cortical thinning (reduced neuron count). So to make a long story short, some of the most severe behavior symptoms and hyperactivity can significantly diminish over time while the core autism symptoms remain.

      Also, inflammation begets inflammation so long-term use of NAC may have helped his amygdala and hippocampus get back to a healthier steady state. Whether this all deteriorates over time without NAC is impossible to say, but it does not hurt to see how things go without it for a while. Also, other interventions can achieve many of the same goals as with NAC. I found that Biogaia Gastrus significantly reduced rage and hyperactive symptoms, but that going without it for a week led to increased behavior problems (we recently went on vacation and I could not ferment with milk the Biogaia Gastrus like I usually do so lets just say there were some challenges till we got home).

      Delete
    2. Hi Nancy,

      NAC can block dopamine release, yet is protective on dopamine systems at the same time (it prevents excessive release).

      There are lots of papers available on pubmed about this, go have a search.

      I have found NAC can make me 'too stable' and takes the joy out of life (especially above 1200mg, 600mg I seem to be fine), with no joy in life what is worth living for.

      Delete
    3. Nancy, NAC has many biological effects, generally good ones. I know your son is an adult, but 4.8g is a lot of NAC.

      I would make a pause from NAC, until any of the old problematic behaviors may return. If that happens restart NAC with a lower dose. I use 2.4g a day, which is actually less than I gave four years ago.

      Delete
  11. Hi Aspie1983, thanks for letting us know how Nac makes you feel. Since I can't feel how my son feels, I had noticed the "too stable" effect you describe from Nac but couldn't define it and said that I had mixed results. When I found out that it can block dopamine I stopped it because I want nothing to antagonise his dopamine anymore, he had already suffered a lot from antipsychotics.
    Do you use melatonin for your sleeping difficulties? Do you know if melatonin can affect dopamine? It is also a great antioxidant but I am wondering if it could make things worse with anhedonia.

    ReplyDelete
    Replies
    1. Petra do you mind if I ask what led to your son being on antipsychotics?

      Delete
    2. Tanya, you know, when someone presents with psychotic like symptoms doctors prescribe antipsychotics to minimize aggression and delusional behaviour.
      There is the "dopamine hypothesis" model of psychosis attributing the symptoms to a hyperactive dopaminergic signaling, particularly D2.
      So as far as I know, this is followed by the "normal science paradigm".
      For example, when my 12 year old nephew started being aggressive he was given Risperdal and my 17 year old niece, bipolar(?) is on Seroquel. My son was on Olanzapine because the first line treatment Risperdal gave him headaches and Olanzapine seemed well tolerated back then.

      Delete
    3. Thank you Petra. I am new to all of this anti psychotic recommendations for autism. It does seem to be the "normal science paradigm" but I was just wondering if only recommended for autism aggression/property destruction when there is a family history with bi polar. My nephew is bi-polar/schizo affective and started showing signs at age 18. Was your son having delusional behavior? It seems to be like a switch flipped in my son. We are trying to get it figured out now - he is under a team of doctors' care, psychiatric, neuroscientist with several phDs, and medical staff looking in to mold toxicity etc. I think everyone with a child on spectrum needs to watch carefully during entire time of adolescence as well as in to early 20s. Clearly avoiding seizures is not the only target by this age. Thank you for sharing what you do. I pay careful attention to your reports and commentary, as well as Aspie's. I know my son has a different diagnostic label than your son, his is "autism", but there are many things he has in common with what you have shared about your son.

      Delete
    4. Peter, btw, a little anecdote here: everything that has been happening recently with my son I have suddenly come down with icy cold hands and feet. I am chalking that up to intense anxiety in me. So that could simply be it for many on the spectrum?

      Delete
    5. Tanya, could you describe what happened to your son when you say "like a switch flipped". From your previous posts, your son is very similar to mine. Mine is 8yo. His dopamine system is dis-regulated: he suffers from lack of attention and motivation, but if if we give him anything that raises dopamine (e.g. Ritalin), he becomes angry and self-injurious. I have read several stories where autistic kids become psychotic / schizophrenic in just a week time frame, like a switch, and stay that way.

      Delete
    6. The doctor would probably say not really a switch flipped but it was that way to us with the ritualistic OCD and some manic-like episodes. This was not responsive to zithromax and amoxicillan and other herbal antibiotic I have used in the past for PANDAS/PANS flares. It was very intense and ritualistic OCD we never saw before.

      Delete
    7. Tanya, when sudden behavioral changes occur one possible solution is 5 days of oral steroids (prednisone). This is not long enough to cause troubling side effects. This worked for us last December, when loud verbal tics appeared overnight.

      Delete
  12. Hi Petra,
    Not a problem, sometimes its easy to think more is better with meds/supplements.
    With regards to melatonin, believe it or not I absolutely respond HORRIBLE to it, I feel weirded out so to speak for about 1-2 hours after ingestion (even at only 300MICROgram), the next day I seem to get rebound insomnia.

    Ive discussed this on multiple forums and some people kept pretending im some fool saying there is no negative feedback for melatonin production, well it clearly messes with my sleep (the 2nd day I take it doesnt even work anymore!).

    It is well known to that some forms of autism there is a genetic error with transforming serotonin into melatonin.

    AANAT and n-acetylserotonin

    https://en.wikipedia.org/wiki/Aralkylamine_N-acetyltransferase
    https://en.wikipedia.org/wiki/N-Acetylserotonin

    "NAS has been shown to act as a potent -->> TrkB receptor agonist <<--, while serotonin and melatonin do not."

    TrkB is extremely important for learning.

    "NAS acts as a potent anti-oxidant, NAS effectiveness as an anti-oxidant has been found to be different depending on the experimental model used, it has been described as being between 5 AND 20 TIMES MORE EFFECT THAN MELATONIN AT PROTECTING AGAINST OXIDANT DAMAGE!!!."

    "NAS has been shown to protect against lipid peroxidation in microsomes and mitochondria."

    So in 'normal people' with a properly working circadian rythm and genes, during darkness when AANAT gets active and N-acetylserotonin starts forming it is potently protecting your brain and prepairing you for sleep (where more repair happens), people with autism have malfunctions here, you can easily imagine how not having optimal sleep day in day out year in year out can wreck someones brain aswell.

    This is no surprised as cyclic AMP (cAMP) and PKA (Protein Kinase A) are necesarry in this pathway to do the conversions (and just like Peter has posted before about cAMP being low in some autism forms).

    The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259991/

    Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478596/

    Also the following, unrelated to melatonin though I think:

    N-acetyl aspartate (note this is not NMDA!) in autism spectrum disorders: Regional effects and relationship to FMRI activation
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477551/

    Also a N-Acetyl group (seems hard time forming N-Acetyl groups?)


    Clorgiline - https://en.wikipedia.org/wiki/Clorgiline

    "The SSRI fluoxetine and the MAO-A inhibitor clorgyline upregulate AANAT indirectly through serotonergic mechanisms and thereby increase NAS levels after chronic administration, and this correlates with the onset of their antidepressant effects."

    It is also a high affinity sigma1 agonist.

    If melatonin works for your son definatly keep using it I think, however I personally respond horribly to it.

    ReplyDelete
  13. This article on ARID1B has a released embargo and will appear in May this year. But, from the available abstract, there might be some interesting conclusions to draw:

    "Arid1b-heterozygous mice exhibited abnormal cognitive and social behaviors, which were rescued by treatment with a positive allosteric GABAA receptor modulator."

    https://www.ncbi.nlm.nih.gov/pubmed/29184203

    /Ling

    ReplyDelete
    Replies
    1. Ling, can you use sci-hub where you live? It is very helpful.

      http://sci-hub.tw

      It works, but you need to enter DOI number instead of the title.

      Sci-hub repository has this article.

      Delete
    2. That link will be very helpful indeed. Thank you!
      /Ling

      Delete

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