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Thursday, 17 August 2017

Viruses, Bacteria, Fungi, Parasites and Altered Gene Expression, Relevant to Autism






Today’s post started life as a review of how some viruses affect gene expression and may help cause, or just trigger flare-ups in, some neurological disorders ranging from autism to MS (multiple sclerosis). 
Some people with autism are treated with anti-viral drugs and, anecdotally, some do respond well.  This is not yet an area with hard facts and definitive clinical trials.  
It is actually better to first take a few steps back and consider how all microorganisms can play a role in human health by modifying the gene expression of the host (which is you).  There are four broad categories of microorganism.
Each type of microorganism can be countered by a matching category of pharmaceutical.

·        Antibacterials/antibiotics for bacteria

·        Antifungals to kill or prevent further growth of fungi

·        Antivirals to minimize (but often not eradicate) viruses

·        Antiparasitics to kill parasites  (protists)

All of the above categories of microorganism can affect the expression of multiple genes. By either up or down-regulating important genes at critical times during development, long lasting effects can be created, or there may be just transient effects.
Changes in gene expression likely play a role in many neurological conditions and in particular in what I call “flare-ups”, for example in autism, PANS, PANDAS and indeed schizophrenia.
Not all changes in gene expression are bad. The TSO parasites that do seem to help some people’s autism, by down regulating their immune response, very likely are modifying the host’s gene expression, which then reduces their immune response. This is the mechanism developed by the parasite to protect itself from the host (you) and ensure it is not eradicated.
Steroids affect the expression of multiple genes. When a bacteria of virus triggers PANDAS/PANS the positive effect of steroid therapy may well be by “resetting” the expression of certain important genes.  Here again, even though PANDAS/PANS is now treated clinically in the US, much remains unknown.
For those interested, earlier this summer revised treatment guidelines were published for PANDAS/PANS.

In "Part I–Psychiatric and Behavioral Interventions," Margo Thienemann, MD, Stanford University and coauthors present consensus guidelines for treating the psychiatric and behavioral symptoms of children with PANS/PANDAS. Symptom improvement is aimed at decreasing suffering, improving functioning, and making it easier for the children to adhere to therapeutic interventions.

In "Part II–Use of Immunomodulatory Therapies," Jennifer Frankovich, MD, and coauthors provide recommendations to help guide the use of therapies targeting the neuroinflammation and post-infectious autoimmunity that are common in PANS-PANDAS.

In “Part III–Treatment and Prevention of Infections," Michael Cooperstock, MD, MPH, University of Missouri School of Medicine (Columbia) and coauthors representing the PANS PANDAS Consortium, present a consensus guideline for managing the infection components of these neuropsychiatric conditions.

There is research on what virus/bacteria affects which specific gene, but this area of science is in its infancy.
MS (Multiple Sclerosis) a condition that features faulty remyelination, is likely a much simpler condition than autism and yet nobody knows for sure what causes it. It has been suggested that a virus may be the trigger of at least some types of MS, but researchers are decades away from proving anything. So when it comes to microorganisms and autism, it is mainly a case of speculation and the odd N=1 case study. 

Viral triggers of multiple sclerosis 


The relationship between infections and autoimmune diseases is complex and the mechanisms by which infectious pathogens could trigger MS are likely dynamic, i.e., they might change over time and not be mutually exclusive. Epidemiological observations indicate that viral infections could contribute to MS development not only as triggers of disease exacerbations but also as etiological agents, i.e., long before the disease becomes clinically apparent. The two- to three-folds increased risk of developing MS among individuals with history of IM compared with subjects who acquired EBV without symptoms, the almost universal seropositivity for EBV in adults and children with MS, and the steep and monotonic increase in MS risk with increasing titers of antibodies to EBV in apparently healthy adults could suggest that EBV infection is causally linked to MS development. The mechanisms responsible for this association are far from understood. Moreover, the incidence of IM in Western countries (≥ 5%)  exceeds the prevalence of MS in comparable populations (0.1%) by far (more than 50-fold) suggesting that yet unidentified genetic and/or additional environmental factors determine whether symptomatic EBV infection indeed predisposes to MS.

Although one particular MS-causing agent might still be discovered, current data suggest that multiple infections along with noninfectious environmental factors trigger the development of MS. These factors are likely ubiquitous, i.e., highly prevalent in the general population, and they require a permissive genetic background that predisposes for MS development. Future studies investigating infectious pathogens in a complex and heterogenous disease such as MS will benefit from careful and detailed clinical, pathological, and neuroimaging-based patient characterizations and from reproducibility in different study populations. In addition, novel humanized animal models of autoimmune diseases that are simultaneously permissive for viral pathogens which usually infect only humans  should allow investigation of specific aspects of host–pathogen interactions during autoimmune CNS inflammation in vivo. The integration of these data might eventually allow us to better define the role of viruses in the etiology and pathogenesis of MS and how virus–host interactions could be targeted for MS therapy.  

The ubiquitous human herpesvirus 6 may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. These findings may help explain the differences in severity in symptoms that many people with the disease experience
What is still not fully understood is the relationship between the extent of the viral infection in the brain and the severity of diseases like multiple sclerosis and other demyelinating diseases such as leukodystrophies and Vanishing White Matter disease. For example, do the number of infected cells need to reach a certain threshold before OPC function is impeded? Are individuals who have congenital HHV6 more vulnerable to severe forms of these diseases?
"More research is needed to understand by which mechanisms the virus impedes the function of OPCs and what impact this has on the progression of these diseases," said Mayer-Proschel. "But it is clear that HHV6, while not necessarily the cause of demyelinating diseases, is limiting the ability of the brain to repair damage to myelin thereby potentially accelerating the progression of these diseases."  

Mainstream and “Alternative” Research  
Not all published research fits with the current mainstream scientific consensus. The mainstream is clearly moving towards the realization that all kinds of things can affect gene expression. One currently fashionable area is the gut microbiota, as in this article:-

Some researchers develop hypotheses that go much further, like this one regarding autism’s elder brother, schizophrenia.


Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

And this one by the same author:-

Herpes simplex virus 1 (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk-promoting polymorphisms (also present in control populations), any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This data set is heavily enriched in the susceptibility genes for multiple sclerosis (P = 1.3E-99) > Alzheimer's disease > schizophrenia > Parkinsonism > depression > bipolar disorder > childhood obesity > chronic fatigue > autism > and anorexia (P = 0.047) but not attention deficit hyperactivity disorder, a relationship maintained for genome-wide association study data sets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome data sets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk-promoting effects of the genes whose function it disrupts.

Back to Autism
As we have seen previously in this blog, autism is usually polygenic, meaning very many different genes are affected. This does not mean that anything is necessarily defective in those genes, it just means those genes are either over or under-expressed, this means you end up with either too much, or too little, of whatever that gene makes.
So for a polygenic condition, where in one person hundreds of your 22,000 individual genes are likely over or under-expressed, we really do not want anything to come along and further miss-express critical genes.
Many genes are inter-related and so miss-expression of one can trigger a wave of further effects. This can be either good or bad.
The science is still in its infancy, so it will be many decades before it is translated into medicine, but we can certainly already say what may be happening.
The interactome is a relatively new word to describe the whole set of molecular interactions in a particular cell.
 For example, the well-known bacteria H.pylori that can cause stomach ulcers:- 

Over 1,200 interactions were identified between H. pylori proteins, connecting 46.6% of the proteome.

Just this one common bacterium affects half of the entire set of proteins expressed by a genome (the so called proteome).
So we should not be surprised if some bacteria or viruses have a bad, or indeed good, effect on autism.
This also bring us back to the idea of the holobiont and hologenome, which was introduced in an earlier post. The idea is that what really matters in human health is not just your genome, but the totality of what surrounds you, so that means everything living in you, on you and around you. That includes bugs, bacteria and also those of your pet dog.
All of these factors influence how your genes are expressed. During evolution your body has got used to things and if you make rapid changes, you may indeed upset the balance. So while chlorinating water may have an overall good effect, by killing all those bacteria your body had been expecting, there may be some negative effects. Humans evolved living close to animals, be it dogs or farm animals. We saw earlier that pregnant mothers who live with pets produce children with a lower incidence of asthma.
We also reviewed the hygiene hypothesis, which basically says that a bit of dirt is good for you.
So this post, rather than narrowing things down, really broadens them out.  Everything affects everything.  If you rock the evolutionary boat, don’t be surprised if strange things happen.
Taking Somali refugees to live in Sweden increased their incidence of autism. Is that really a surprise? Recall the Somali autism clusters in Sweden and San Diego.
Apparently, the Amish in the US have a low prevalence of autism. Is that really a surprise?  One reader recently suggested sending autistic people to live with the Amish, as a therapy. The possibly effective therapy would have been to send the parents to live with the Amish for a couple of years before the child was born.
So perhaps we should consider much autism, and indeed conditions like asthma, as collateral damage from modern living?  Life expectancy has risen, infant mortality has been greatly reduced, but the downside is that we now have much more autoimmune disease and that includes autism.

Autism and Microorganisms
Now back to autism and the four categories of microorganism.
Can parasites cause autism? Actually we know they can; for example cerebral malaria can result in it. But how often is this case? Probably very rarely.
Can fungi cause autism? Perhaps, but we know from many examples (including in the comments on this blog) that some fungi can make autism worse.  Is the fungus candida albicans growing in the intestines really an issue in most autism? I seriously doubt it, but oral thrush/candidiasis caused by inhaled steroids does seem to make autism worse and is reversible by removing the fungus. The effect seems more likely to be from the candida than the steroid, since inhaled steroids only mildly enter the bloodstream.
Can bacteria cause autism? Well streptococcus bacteria can cause OCD and cognitive impairment (PANDAS).
Can a virus cause autism? Antonio Persico, one of the more serious autism researchers, has suggested that some autism may be caused by polyomaviruses transmitted at conception from father to mother.
https://spectrumnews.org/news/could-a-virus-cause-autism/

Can the rubella virus cause autism? Some serious people do see a possibility, even in people who have been vaccinated.

These both remain controversial hypotheses; but can viruses cause flare ups in autism, later in life? This is also controversial, but I think quite plausible.  It all depends which genes the virus causes to get miss-expressed.
Enough is known to say that odd changes in autism may potentially be triggered by the appearance of specific types of microorganism, but quite possibly most microorganisms have little, or no, negative effect in most people. So it is not a case of all viruses/bacteria will make autism worse, but it is likely true that some may have the potential to do so.
In trying to figure out possible causes of autism flare-ups, due consideration should be given to microorganisms.  This is another case of personalized medicine, with all its potential pitfalls.
The big risk is potentially becoming obsessed with non-existing bacteria, viruses, fungi or parasites.  


Back to Antivirals and Autism 
Finally we come back to where the original idea for this post came from; is there any basis of the use of antiviral drugs to treat autism?
DAN-type doctors do prescribe the antiviral drugs Valtrex, Famvir or Acyclovir.


Antiviral drugs do not destroy their target virus they just inhibit its development.
Most of the antiviral drugs now available are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A and B viruses.
You identify a virus by looking for antibodies to that specific virus in the blood. You can test for antibodies that suggest if the infection is new and active, called IgM antibodies and you can test for antibodies that show the infection occurred sometime in the past, called IgG antibodies.
You would need to know which virus to test for, the common ones are:-

HSV 1:  Herpes Simplex Virus 1 causes canker sores in the mouth

HSV 2: Herpes Simplex Virus 2 causes genital herpes.

HHV 6: Human Herpes Virus 6 is commonly known as Roseola virus

EBV: Epstein-Barr Virus, causes the illness known as infectious mononucleosis

Measles

Rubella  


“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus.” 

Conclusion: Rate of contact with HSV1 and HSV2 assessed by the mean of detection of specific antibodies was similar between children with ASD and healthy controls.

Conclusion: Levels and seropositivity rate of antibodies to HHV-6 and HHV-8 do not differ between children with ASD and controls.
CONCLUSION: Titre and seropositivity rate of antibodies to CMV and EBV are similar between children with ASD and healthy controls.


Valtrex 
Valtrex seems to be the antiviral most commonly prescribed in autism.  This is an off-label use, meaning Valtrex is not approved to treat autism.  Valtrex is active against most species in the herpesvirus family. In descending order of activity:

So we might assume the people with autism who respond to Valtrex might have one of the above, or similar, viruses. Unless Valtrex has some other modes of action, unrelated to being an anti-viral, which remains a possibility. 

Mitochondrial Disease and Viral Infections
Since this post is already full of speculation, I will add some more. Some people say that their child’s mitochondrial disease was preceded by a viral infection, so how likely is it that a virus can trigger mitochondrial disease and then autism?  Again, this is not something anyone can prove, one way or the other, but it does look like your mitochondria are particularly vulnerable to viruses.
The virus will exploit the mitochondria to further its own development, perhaps in doing so, in some people with a pre-disposition, this triggers a process to chronic mitochondrial dysfunction.  Read the papers below for more on this subject.


Highlights


Mitochondrial dynamics influences mitochondrial and cellular functions.
Mitochondrial dynamics is affected during viral infections.
Viruses exploit mitochondrial dynamics and mitophagy to benefit infectious process.
Virus-altered mitochondrial dynamics determines the outcome of infection.
Disruption of mitochondrial dynamics promotes viral pathogenesis.

If a virus can trigger mitochondrial disease, as we have seen a vaccination can, is there any possible merit in using antivirals years later?
Is there merit treating regressive autism, which is likely to be mitochondrial disease, immediately with antiviral drugs?
Is there merit treating autism flare-ups, that do not respond to PANDAS/PANS therapies, with antiviral drugs?
Is there merit treating MS (multiple sclerosis) immediately on diagnosis with antiviral drugs? Would MS flare-ups respond to antivirals?

My take
If I was to develop MS tomorrow, given there is currently no cure, I think I might want to try an antiviral, just in case it might actually do some good.
My son with classic autism did have a PANDAS-like regression last year, with sudden onset OCD and strange verbalizations. It all went away after a couple of weeks, having been treated as a PANDAS flare-up, as documented in an old post on this blog. If after a viral infection he developed a sudden onset regression I would certainly reread this post.
Readers of this blog with a clear case of mitochondrial disease might want to check for the commonly implicated viruses, since if one was never suppressed this might be something to consider.
So do antivirals have a place in treating autism?  There is no hard evidence to support their use, but I would not at all be surprised if a minority do genuinely benefit. I think the most likely group might be those who have a sudden regression from near typical. As with PANDAS/PANS, the sooner the treatment commences, the better the likely outcome. 
Could antivirals help control flare-ups that can occur in those already with autism? They could well help; ideally you would confirm the presence of the virus first.   

Conclusion
I recently watched an expert clinician talking about irritable bowel syndrome (IBS); he was very open about his opinion that science likely only understands about 30% of the disorder. When it comes to autism I think science may be only at the 10% mark. As a result you have to be very careful about saying anything definitive.
We know that very many things contribute to the prevalence of autism.  It looks more than likely that viruses, bacteria, fungi and parasites may, on occasion, play a role in some people’s autism.
But, just like we know that in some people vaccination can trigger mitochondrial disease and result in an autism diagnosis, this does not mean it is a common cause of autism. Vaccinations have saved hundreds of millions of lives, but it has long been known that they can have side effects and that is why there is a large industry-funded compensation scheme in the US.
So while parasites can in some circumstances lead to autism, this does not mean feeding bleach to children with autism is a clever idea. Nor does filling them with antibiotics to treat a non-existing bacteria.
You can see why mainstream medicine is not eager to treat autism.
Nonetheless, applying that meagre sounding 10% of understanding can yield results, when applied with caution.










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Thursday, 27 July 2017

Targeting Dendritic Spines to Improve Cognitive Function and Behavior in Autism; plus Hair Loss/Graying



I have written several posts about dendritic spines and their varying shapes (morphology).  This sounds like a rather obscure subject, but it looks like it may be a key area where both behavior and cognition can be modified, even later in life.



Homer Simson after using a Wnt Activator 

Dendritic spines

In a typical neuron (brain cell) you have dendrites at one end and so-called axon terminals at the other. When neurons connect with each other, an axon terminal connects with a dendritic spine from another close by neuron.  Axons transmit electrochemical signals from one neuron to the dendrites of other neurons.  The junction formed between a dendritic spine and an axon terminal is called a synapse.







 One neuron can have as many as 15,000 spines, some of which are picking up signals from axon terminals of other neurons.
The number and shape of these spines is constantly changing and not surprisingly defects in this process affect both cognition and behavior.
The other end of the neuron, with the axon terminals is much less studied.  The myelin sheath deserves a mention. This protective coating is constantly being repaired in a process called remyelination. MS (Multiple Sclerosis) is caused by damage to the myelin coating that does not self repair. A newly identified feature of autism is an abnormally thin layer of myelin. A lack of insulation along the axon will affect the flow of electrical signals.
Many factors are involved in dendritic spine morphology and plasticity. Many of the same factors are known to be disturbed in autism and other related dysfunctions (schizophrenia, bipolar, ADHD etc).
Recall that within autism there are two broad groups; the larger group has “too many” dendritic spines and the smaller group has “too few”. I am writing about the larger group. My post is a simplification of a complex subject.
Factors that influence dendritic spine morphology and plasticity include:- 

·        BDNF  (want less)

·        Estrogen  (want more)

·        Reelin (want more)

·        BCL2 (want more)

·        PAK1 (want less)

·        GSK3 beta (want more)

·        PTEN (want more)

All the above seem to work via

·        Wnt signaling (want less) 

BDNF is a growth factor within the brain, which tends to be elevated in most autism.
The female hormone estrogen seems to be reduced in male autism and this will have many effects via something called ROR alpha. There is also reduced expression of estrogen receptor beta.
Reelin is a protein that is critical in brain development and maintenance. Reelin is implicated in most brain diseases, including autism. It stimulates dendritic spine development. Reelin is found to be reduced in autism.
BCl2 is a very well-known cancer gene/protein. BCL2 is part of a broader family of genes/proteins that control cell growth/death. BCL2 is anti-apoptotic, meaning it encourages growth rather than cell death. You will find elevated BCL2 in cancers.  BCL2 is implicated in both schizophrenia and autism.
Bax is another key member of the BCL2 family. The BCL2 protein duels with Bax, its counteracting twin. When Bax is in excess, cells execute a death command. When BCL2 dominates, the program is inhibited and cells survive. In cancer you want more Bax.
Modulating BCL2/Bax has been proposed as an autism therapy in Japan.
BCL2 is found to be reduced in autism.
The Japanese proposed the use of Navitoclax, a drug responsible for inhibiting BCL2 production for the treatment of cancer. I think they want to activate BCL2 production. 
I covered PAK1 in some lengthy posts. This was what the Japanese Nobel Laureate at MIT was working on. In summary, a PAK1 inhibitor should be helpful in autism, schizophrenia and some cancer.  Some people with a condition called neurofibromatosis, where non-cancerous tumors grow, use a special kind of bee propolis that contains a substance called CAPE (caffeic acid phenethyl ester), that is a mild PAK1 inhibitor.


GSK3 beta plays a role in several key signaling pathways. Abnormal expression of GSK3 beta is associated with Bipolar disorder. One role played by GSK3 beta is in Wnt signaling, which then affects dendritic spines. A GSK3 beta inhibitor, like lithium, is a Wnt activator which will increase the number of dendritic spines.
PTEN is a tumor suppressor gene/protein that is also an autism gene.
PTEN deficiency results in abnormal arborization and myelination in humans. PTEN-deficient neurons in brains of animal models have increased synaptic spine density.
People with autism and PTEN mutations have large heads because they lacked enough PTEN to reign in cell growth (and head growth).  You would expect them to have increased synaptic spine density.
Note than in both autism/cancer genes (BCL2 and PTEN) the balance is shifted towards growth, which fits in with the broad concept of autism as a growth dysfunction.
Wnt signaling is a complex and only partially understood subject, that has been previously discussed in this blog.  The short version is that most people with autism and particularly the ones with large heads will likely have too much Wnt signaling as the result of their various metabolic “disturbances”. The best way to inhibit their Wnt signaling might be to counter their particular metabolic disturbances, so if you are one of the 2% of autism with a PTEN mutation, then increase your PTEN levels.  If this is not possible than any other way to inhibit Wnt might be effective.
In Bipolar, where GSK3 beta is a known risk gene, you want more dendritic spines and so you want a GSK3 beta inhibitor like lithium. 
I think lithium will have a negative effect on most autism. Within children diagnosed with autism, a minority may well better fit a diagnosis of bipolar.

OBJECTIVE:


Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD.

METHODS:


We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score ≥3).

RESULTS:


Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70 mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%).

CONCLUSIONS:


This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.


Hair Growth and Graying 
One surprising observation is the apparent connection between dendritic spine modification and modifying growth/color of human hair.
The same pathway is involved in signaling growth and coloring in the hair on your head and growing the dendritic spines on the neurons inside your head. I have mentioned this once before in a previous post. It is relevant because if a substance is potent enough to affect your dendritic spines you would expect it also to have a visible effect on the hair, of at least some people.
For example one reader of this blog uses a PAK1 inhibitor to treat her case of autism and she found that it has a hair graying effect.

EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

Pigmented hair regeneration requires epithelial stem cells (EpSCs) and melanocyte stem cells (McSCs) in the hair follicle.

Thus far, only a handful of signals that regulate McSCs have been identified, including extrinsic signals, such as transforming growth factor beta (TGFB) and Wnts, which are provided by the epithelial niche. Wnt signaling induces activation of EpSCs to drive epithelial regeneration while coordinately inducing McSCs to proliferate and differentiate to pigment regenerating hair follicle


One known but uncommon side effect of my current favourite Wnt inhibitor, Mebendazole, is hair loss. Hair follicles require Wnt signaling and if there is too little Wnt signaling you will lose some hair.
BCL2 is a very important cancer gene/protein but it also plays a role in autism and in dendritic spine morphology.  Low levels of the protein BCl2 leads to premature graying.

The team then looked at what would happen if they 'knocked out' a gene in mice that is known to be important for cell survival.
Mice lacking this Bcl2 gene went grey shortly after birth.

The scientists believe the same principle might apply in humans, which would explain why some people - such as TV presenter Philip Schofield - go grey in their 20s, while others keep their dark locks into retirement.
  

BCL2 is known to be reduced in the reduced in the brains of people with autism, as is another substance called Reelin.  Both Reelin and Bcl-2 are needed for dendritic spines to develop correctly.  

Autism is a severe neurodevelopmental disorder with potential genetic and environmental causes. Cerebellar pathology including Purkinje cell atrophy has been demonstrated previously. We hypothesized that cell migration and apoptotic mechanisms may account for observed Purkinje cell abnormalities. Reelin is an important secretory glycoprotein responsible for normal layering of the brain. Bcl-2 is a regulatory protein responsible for control of programmed cell death in the brain. Autistic and normal control cerebellar corteces matched for age, sex, and post-mortem interval (PMI) were prepared for SDS-gel electrophoresis and Western blotting using specific anti-Reelin and anti-Bcl-2 antibodies. Quantification of Reelin bands showed 43%, 44%, and 44% reductions in autistic cerebellum (mean optical density +/- SD per 30 microg protein 4.05 +/- 4.0, 1.98 +/- 2.0, 13.88 +/- 11.9 for 410 kDa, 330 kDa, and 180 kDa bands, respectively; N = 5) compared with controls (mean optical density +/- SD per 30 microg protein, 7.1 +/- 1.6, 3.5 +/- 1.0, 24.7 +/- 5.0; N = 8, p < 0.0402 for 180 kDa band). Quantification of Bcl-2 levels showed a 34% to 51% reduction in autistic cerebellum (M +/- SD per 75 microg protein 0.29 +/- 0.08; N = 5) compared with controls (M +/- SD per 75 microg protein 0.59 +/- 0.31; N = 8, p < 0.0451). Measurement of beta-actin (M +/- SD for controls 7.3 +/- 2.9; for autistics 6.77 +/- 0.66) in the same homogenates did not differ significantly between groups. These results demonstrate for the first time that dysregulation of Reelin and Bcl-2 may be responsible for some of the brain structural and behavioral abnormalities observed in autism.  

Abstract

The development of distinct cellular layers and precise synaptic circuits is essential for the formation of well-functioning cortical structures in the mammalian brain. The extracellular protein Reelin through the activation of a core signaling pathway including the ApoER2 and VLDLR receptors and the adapter protein Dab1, controls the positioning of radially migrating principal neurons, promotes the extension of dendritic processes in immature forebrain neurons, and affects synaptic transmission. Here we report for the first time that the Reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons. Our data underscore the importance of Reelin as a factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus. These findings may have implications for understanding the origin of cognitive disorders associated with Reelin deficiency.

While not everything relating to dendritic spines is variable, and hence potentially can be modified, much seems to be.
Rather like in this blog it took a few years to get a comprehensive view of the factors involved in neuronal chloride and extend the list of potential therapies, getting to the bottom of fine tuning dendritic spin morphology for improved behavior and cognition will be a complex task.
Much is already known.
Our reader AJ is busy looking at GSK3 beta inhibitors.
GSK3 beta is best known as a bipolar gene/protein, but it is becoming seen as an autism gene.


GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated β-catenin phosphorylation is known to be the key event in Wnt-β-catenin signaling, the mechanisms which underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-β-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.
Recent advances indicate that GSK3 also plays a positive role in Wnt signal transduction by phosphorylating the Wnt receptors low density lipoprotein receptor-related protein (LRP5/6) and provide new mechanisms for the suppression of GSK3 activity by Wnt in β-catenin stabilization. Furthermore, GSK3 mediates crosstalk between signaling pathways and β-catenin-independent downstream signaling from Wnt.


it is known that glycogen synthase kinase 3β (GSK-3β) regulates both synaptic plasticity and memory. 
GSK-3β overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased.


Over the past 2 decades, neuroscientists have built a body of evidence that links not only bipolar disease, but other psychiatric disorders including autism and schizophrenia to abnormal brain development. In particular, they have found abnormalities in the numbers of synapses and in the shape of neurons at the points where they form synapses. Their studies have often implicated abnormal signaling in a brain pathway called Wnt, which is involved both in early brain development and later, more complex, refining of brain connections. The role of Wnt could help explain why lithium is effective: It blocks an enzyme called GSK-3 β, which is an inhibitor on the Wnt pathway. By boosting Wnt signaling, lithium could produce a therapeutic effect in psychiatric diseases in which the Wnt pathway is underpowered.

They then treated the mutant mice with lithium. Although the researchers acknowledge that rodents are an imperfect proxy for human mood disorders, they did observe that the animals’ symptoms markedly improved; studies of their brains also revealed normal numbers of spines. “That’s the key finding,” Cheyette says. “It suggests that lithium could have its well-known therapeutic effect on patients with bipolar disorder by changing the stability of spines in the brain.”
GSK3 has numerous effects.

Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/β-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3.  

Estradiol


The present study demonstrates that estradiol may trigger formation of new dendritic spines by activation of a cAMPregulated CREB phosphorylation. Induction of the CREB response requires activation of NMDA receptors, increased intracellularcalciumconcentrationsandcAMP-activatedPKA.These systems together then contribute to the CREB response, which in turn leads to the morphological changes seen with estradiol—i.e., spine formation. The biochemical and cellular routes leading from activated CREB to the morphological change in dendritic spine density are still uncharted.

Dendritic spines of the medial amygdala: plasticity, density, shape, and subcellular modulation by sex steroids.

The medial nucleus of the amygdala (MeA) is a complex component of the "extended amygdala" in rats. Its posterodorsal subnucleus (MePD) has a remarkable expression of gonadal hormone receptors, is sexually dimorphic or affected by sex steroids, and modulates various social behaviors. Dendritic spines show remarkable changes relevant for synaptic strength and plasticity. Adult males have more spines than females, the density of dendritic spines changes in the course of hours to a few days and is lower in proestrous and estrous phases of the ovarian cycle, or is affected by both sex steroid withdrawal and hormonal replacement therapy in the MePD. Males also have more thin spines than mushroom-like or stubby/wide ones. The presence of dendritic fillopodia and axonal protrusions in the MePD neuropil of adult animals reinforces the evidence for local plasticity. Estrogen affects synaptic and cellular growth and neuroprotection in the MeA by regulating the activity of the cyclic AMP response element-binding protein (CREB)-related gene products, brain-derived neurotrophic factor (BDNF), the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and the activity-regulated cytoskeleton-related protein (Arc). These effects on signal transduction cascades can also lead to local protein synthesis and/or rearrangement of the cytoskeleton and subsequent numerical/morphological alterations in dendritic spines. Various working hypotheses are raised from these experimental data and reveal the MePD as a relevant region to study the effects of sex steroids in the rat brain.

PTEN 


CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3β. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.  


Mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology using fluorescent dye confocal imaging. Contrary to previous studies in dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory post-synaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors. 


Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.

BDNF
A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.


Other Wnt inhibitors

Yet another anti-parasite drug, Niclosamide,  turns out to be a Wnt inhibitor. 


Not surprisingly, Niclosamide is now a candidate drug to treat several different types of cancer.  It is also thought to have great potential in suppressing the metastatic process of prostate cancer. Another extremely cheap drug, not available in the US.
Even the flavonoid quercetin can inhibit Wnt. 

Therapeutic Avenues

There certainly are many potential ways to fine tune dendritic spine morphology.
Some readers of this blog are already doing just that, perhaps not all realizing it. 
·        BDNF  (want less - TrkB inhibitor)

·        Estrogen 

·        Reelin (want more – statin via RAS activation)

·        BCL2 (want more – statin)

·        PAK1 (want less – PAK inhibitor, BIO30)

·        GSK3 beta (want more – GSK3 activator)

·        PTEN (want more – statin)

All the above seem to work via

·        Wnt signaling (want less – Mebendazole/Niclosamide etc)

If you inhibit GSK3 beta you activate Wnt. You need get things the right way around. 
Statins promote RAS signaling which appears to increase Reelin expression. 


Conclusion

Fine tuning dendritic spine morphology seems like a good target for those with MR/ID and also those with any kind of neurological disorder.
There appear to be many ways to achieve this.
It seems a plausible idea and in many ways seems more credible than the idea of a diuretic (bumetanide) raising some people’s IQ.
The big issue is which substances have sufficient potency, once they have crossed the blood brain barrier, to do anything at all.  This is an issue with all therapies targeting the brain, including bumetanide.
At least substances that can affect hair growth and color are making it through to the bloodstream, which is a start.
Does this mean that tuning your dendritic spines will inevitably make your hair turn grey or begin to thin?  I don’t think so. I think this will happen in people who have low to normal Wnt signaling to start with.
Do some people with naturally premature graying, or thinning, hair have low levels of Wnt signaling? Quite possibly. Are they more likely to have traits of bipolar/creativity? Look for actors with gray or thinning hair.
Do people with autism tend to have full heads of thicker hair, as well as bigger heads?
Do the minority of people with autism and small heads have thinning hair?
Some readers of this blog are already using statins to treat autism. As has been pointed out in earlier posts, other than lowing cholesterol, statins have potent anti-inflammatory effects and they also affect expression of RAS, PTEN and BCL2, all of which are implicated in autism and all affect dendritic spines. It seems plausible that these readers are already modifying dendritic spine morphology.




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