Schizophrenia rather than Fragile-X and Retts Syndrome, as a Reference for ASD

You may, like me, have wondered why so much autism research seems to mention Fragile-X syndrome and Retts syndrome.  

Both Fragile-X and Retts are caused by the mutation of single genes, FMR1 and MECP2 respectively.  Autism can be caused by very many, seemingly unrelated things, both genetic and environmental.

When you look at it objectively, there is a much closer comparison for autism, it is schizophrenia.  

I know from the research I am reading that in fact autism and schizophrenia are intertwined and there is no boundary were one stops and the other starts.  Most likely some of the individual biological dysfunctions in autism are present in a greater/lesser degree in schizophrenia and vice versa.  This will be developed in later posts.

For those interested in learning more about schizophrenia here is a nice PowerPoint presentation.

https://files.itslearning.com/data/1512/469/SCHIZO%20PP.pptx

Here are some excerpts:-

·        A biological disorder of the brain which causes disturbances in thinking, speech, perception of reality, emotion (mood), and behavior.

·        Approximately 1% of the population develops schizophrenia during their lifetime.

·        Although schizophrenia affects men and women with equal frequency, the disorder often appears early in men (usually late teens), than women (generally late twenties/early thirties).

The most ASD-like sub-type is called disorganized schizophrenia; and it principal features are:-

•      Confusion and Incoherence

•      Severe deterioration of adaptive behavior

–     Lack of social skills

–     Poor personal hygiene & self-care

•      Behavior appears silly and/or child-like

•      Highly  inappropriate emotional responses

It is not hard to see the potential overlap between ASD and Disorganized Schizophrenia.

We even have a researcher suggesting a very similar strategy for Schizophrenia, to that I am proposing/developing for autism.

Phenotype of schizophrenia: a review and formulation

The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

For psychiatrists, the main difference between autism and schizophrenia seems to be when is the onset of symptoms.  Autism strikes at the age of two or three, whereas schizophrenia occurs much older.  Whether in fact some of the same biological mechanisms might be at work does not seem to be relevant to psychiatrists.  Not surprisingly, they have not made much progress treating either condition.

In the days before the autism was so widely diagnosed, there were many more cases of childhood schizophrenia reported, now it is very rarely diagnosed condition, it became autism.

I did look for some statistics that included autism and schizophrenia, but those clever psychiatrists seem to have separated them, so autism is with developmental disabilities and schizophrenia is not.

But I did find some interesting statistics about developmental disabilities.

When you look at the US statistics (1997 – 2008), based on parent-reported developmental disabilities.

Source:  http://pediatrics.aappublications.org/content/early/2011/05/19/peds.2010-2989.full.pdf+html

You can see that about 15% of kids have some kind of developmental disability.  Cases of autism increase from 0.2% to  0.7% over the ten years, but those with a learning disability is pretty flat at around 7% and mental retardation (MR) / intellectual disability is also pretty flat at 0.7%.

You also see that the incidence of seizures remains flat at about 0.7%.

According to the medical research, about 30% of people with autism will also have seizures; you would expect to see a seizure “epidemic’, if there had been an autism “epidemic”.  Whereas diagnosing autism is highly subjective, recognizing most types of seizure is not.

So clearly the numbers do not add up.  Perhaps now only 10% of people with autism have seizures?  Or perhaps only 30% of people with autism, really have it?   

The same is true with the incidence of mental retardation (intellectual disability) it remains flat at 0.7%.  According to the WHO, 50% of people with autism also have MR.  So, if there had been a big increase in new people with autism, you would expect an increase in MR.  If the level of MR remains flat it would seem that some people with MR have just been given an additional diagnosis of autism.  Either that, or the 50% figure is now much lower in the US, (which is what I expect is the reality).

With even the most basic figures not adding up, is it really surprising how little progress has been made in the hard part – actually finding treatments?

Autism has changed and now means entirely different things, to different people.  In particular, comparisons across countries are completely meaningless.

Schizophrenia

Schizophrenia has also changed and is now considered as a family or spectrum of disorders.

Like autism, nobody really knows what causes schizophrenia and most likely many things do, like autism.  There is no single gene, like with Fragile-X or Retts, and there is no cure.

When researchers compared the mixture of genetic dysfunctions in schizophrenia and autism, they found a clear overlap.  This is interesting and perhaps should not have come as a surprise.

In some ways Fragile-X and Retts are actually the opposite of autism.  For example in the case of Retts, the very important substance, Nerve Growth Factor (NGF), is almost at zero, whereas in autism levels tend to be elevated.

Just as we can learn from the comorbidities of autism, I think we can learn a thing or two from the existing research in Schizophrenia.  Indeed I already have.

MR

If anyone was seriously researching treating Mental Retardation (MR), in physically “normal” people, who have not suffered from a brain infection, toxic exposure, malnutrition or any kind of pre-natal or natal problem, we would have another great resource.  It would probably show that, in some cases, MR is caused by a partially-reversible imbalance in the actions of various neurotransmitters, ion channels, hormones etc.  Some of these imbalances will also exist in numerous cases of autism.

According to the well-known expert, Professor Howlin, only about 20% of people with ASD have an IQ in the normal range (i.e. above 70) and 50% have moderate or greater MR (i.e. IQ less than 50).  It would seem that the missing 30% must have mild MR (i.e. an IQ 50 to 70).

I suspect that the cognitive improvement found by treating some types of autism could be replicated in some cases of MR, without ASD.  If there were any clever therapies for treating MR, I would think they would likely be beneficial in autism.  In most countries, as many children have MR as have ASD, so it is strange nobody is looking how to treat it.  They assume the “defects” are hard-wired into the brain; I looks to me that some are not.

Clinical Trials

Even though ASD is a lifelong condition, nearly all the clinical trials are in children, and most often, in quite young children.  Assessing such people is doubly difficult.  Working with adults should be much easier and provide better quality data.

Other neurological conditions like schizophrenia and bi-polar disorder are regarded as adult conditions, so hopefully the quality of the research data is better.  We will see.

Plenty of adults have ASD and the ones with Asperger’s will have no difficulty articulating the effects of any intervention, so it is a pity they are rarely involved in research. 

   

Conclusion

On a happier note, I believe that if you can tune the autistic brain to its optimal performance, you will see a marked improvement in cognitive ability and, by implication, in measured IQ.  

I have no doubt that a well executed, intensive ABA program, over a few years, could also show a marked improvement in measured IQ, in many cases.  ABA is also a kind of retuning of the brain, but it has to be done right to be effective.

Biological tuning plus ABA should yield the best results.

As for schizophrenia, the biological "overlap" with autism does indeed exist. Two such areas are dysfunctional calcium channels and indeed the glutamate receptor mGluR5.  This will be developed later.

When Less is More - Tuning the Autistic Brain with Clonazepam

   

I cannot say whether there will ever be a “cure” for autism, but this blog has shown that certain types of autism can be treated today.  Actually, it is becoming much more like tuning.

Tucked away in the scientific literature, you can find that some receptors in the brain respond very differently to small stimuli than to large ones, I found this intriguing but thought little more of it.  Then, in the recent post on Glutamate receptors, I saw a chart from the MIT researcher that showed how using drugs you could increase/decrease protein synthesis in the brain, to optimize neural performance.  Rather like tuning the ignition timing on your car, some people were a little ahead of where they should be (Fragile X) and others were a little behind (Rett’s).  By using the right dose of either a positive or a negative modulator (of the mGluR5 receptor) you could tune the brain for optimal performance.

Source: Contributions of metabotropic glutamate receptors to the Pathophysiology of Autism

In the case of a recently investigated GABA dysfunction in autism, the drug is Clonazepam.  Tiny doses of this drug improve the performance of the neurotransmitter GABA, apparently by affecting the Na_v1.1 ion channel.

In the research (on mice) it was shown that, within a tight dosage range, there was a measurable improvement in cognitive behaviour.  Too much, or too little of the drug and this benefit was lost.  So you would have to tune the dosing very carefully to get any effect.

It appears in humans things are more complicated than in mice, the small band of dosage where positive effects are seen does exist also in humans, but at slightly higher doses the effect turns negative before disappearing.

Source: Peter research

  

 This means that you have to get the dosage and timing just right to get the good effect.  Unlike tuning your car, where the effect is immediate, Clonazepam has a half-life of 30 hours.  This means that the concentration in the blood is made up of several doses from the last few days.

This made me realize what a challenge this would be to get right in other people.

I should point out that the same issue applies with TRH.  At the effective (also tiny) dosage you get a nice positive effect, but go too far and you get instant anger.  An Italian-Swiss researcher is using another analogue of TRH to treat some of the effects of aging.  He clearly had the same problem;  too much ended up having a bad effect.  Now he cycles one month on the drug and the next month with none.  TRH has numerous effects in different parts of the body, it has now been suggested that falling levels in middle age triggers hair to start to go grey.

With Clonazepam, along with some cognitive improvement, you also get very good mood, but at slightly higher concentrations happiness is replaced by anxiety. 

The effective Clonazepam dosage seems to fall over time; this is a very good thing, but further complicates getting things just right.  In high standard doses, the effect of Clonazepam normally reduces over time and patients need more of it.  The drug is normally used in doses 20 to 150 times higher to treat anxiety and seizures.

A further complication is that the optimal dose is 8% of the smallest available tablet.  The tablets do not dissolve nicely in water, you get a lumpy suspension.  As a result the dosage is always going to be a bit “hit or miss”

Conclusion

It looks to me that future autism treatment will include “tuning” specific dysfunctions with tiny amounts of drugs.

The good news is that tiny doses are far safer and less likely to have any secondary effects, than large doses.

The bad news is who is going to do the tuning?

People with Asperger’s, some of whom read this blog, will able to tune themselves; for others it will not be so easy.

In the case of Glutamate (mGluR5), the drugs required are still experimental.  In the case of GABA, they already exist.

A Surprise at the Dentist

The dentist is probably the worst place you can imagine to have to take a child with autism.  The same is true with many typical kids and even some adults.

If you talk to older people about their childhood experience at the dentist, before high speed drills and the like, it was more like torture.  Times have changed, it is not just better equipment, but (some) attitudes have changed.

For someone with autism, going to the dentist should not have to be a terrifying experience; people with autism actually have a high pain threshold.  True they have lots of sensory issues, but it seems to be the fact that they do not understand what is going on, that is the real problem.

A better way

There exist some very child-friendly dentists who are more than a match for a child with autism.  They can achieve what seems impossible, a calm and cooperative dental patient, who will sit back and let the dentist do his work.

One such dentist has even made a training program for other dentists to show how to achieve this.  In effect, it is a very practical ABA lesson for dentists.  The dentist is called Dr Tesini and his program is called D-Termined and he is indeed determined to succeed.

Here is clip from Youtube.

 Dr Tesini even teamed up with an autism charity to make a DVD of his method.  It used to be free but now costs $13.

Here is a link to the foundation that funded the program.

I acquired the DVD 6 years ago, but could not find any local dentist interested to apply the method.

The method is great because once the child has got used to the nice friendly Dr Tesini and gone through all the steps, he is apparently then able to “tolerate” the less friendly regular dentists, for future dental visits.

In some special schools they have a dental chair for the kids to practice on, which as another great idea.

 

Monty at the Dentist Five years ago

We have a nice friendly dentist, but I think he felt from the start that working on a child with ASD was going to be too much.  We made a few very brief visits when Monty was four and five years old and even brought along the Dr Tesini D-Termined DVD,  but this really just showed how difficult a task lay ahead if any actual drilling and filling was required.

It was never really clear whether Monty had toothache or not, since he could not verbalize the problem.  So sometimes if he was behaving aggressively, we might think that he had tooth problems.  Later things would calm down and we would forget about teeth and dentists.

In the end I had to find a practical solution.  Were we live there seemed to be no good solutions;  generally people with ASD just have rotten teeth.  A State hospital clinic did in theory offer dentistry under full anesthetic, but it looks like the hospital block of a gulag and there was a three month wait anyway.  Private dentists are not allowed to give sedation or full anesthetic, for safety reasons, just local anesthetic.

Eventually I found a solution in a neighboring country where you could have dental work under general anesthetic, in surroundings that did not look like a prisoner of war camp. Aged five, Monty had his four fillings and one extraction under full anesthetic with a German dentist and a Hungarian anesthetist.  The first part involves an injection into a vein in the arm, even this little step involved a great deal of kicking and screaming (Monty and his Mum).

So as not to repeat this unpleasant, and very expensive, experience too often, I stopped Monty drinking so much fruit juice and came up with a special tooth brushing regime.

One of Monty’s first words, aged about 40 months was “juice” and so pleased were people to hear him use any word, that juice is what he got.  In fact when he said “juice” he really just meant he was thirsty, water would have been just fine.  The acidity of fruit juice rots milk teeth.  Also, at the start of an ABA program, or even PECS program, there are a lot of edible reinforcers (candies) involved; great for speech, but not your teeth.

The teeth brushing regime involved brushing first with a manual brush and then again with an electric tooth brush.  This way there is more chance of not missing anything.

Monty at the Dentist Five Years On

Having not had any dental work for five years and still not having found a dentist who wanted to learn how to treat a child with autism, I was faced again with the undesirable option of full anesthetic.  I hoped that in the subsequent five years there might be some options closer to home.

While it seems that only hospitals can give full anesthetic, one of the small private medical clinics that also do minor surgery, has started to offer dentistry.  So I thought that if they have an anesthetist available for the minor surgery, why can’t the dentist use him?

A few phone calls later, it did indeed seem to be possible.  It clearly was not something they usually did, but the dentist did not think it was a crazy idea.

So last week Monty, myself and his assistant, who teaches him at home in the afternoon, turned up at the clinic.  Expecting to see an older male dentist with a serious face, I was very surprised to see a small slim female dentist and her smiling assistant.  It was as if we had stepped in to Dr Tesini’s training video.

All happy, smiling and fun, the dentist let Monty play with all the buttons and bits of equipment.  She made balloons out of surgical gloves and generally made friends with her new patient.

Her attitude was “why would I need anesthetic to treat such a nice boy”.  She gave him an examination, with Monty being surprisingly compliant.  She concluded that his toothache was caused by his four rear permanent that have yet to emerge.  One of the five year old fillings in his milk teeth looks a bit poor, but the X-ray showed that it is far from the pulp of the tooth.  The tooth should fall out before the filling fails.

In fact the only intervention is protective fissure sealant on four permanent teeth and ultrasonic de-scaling his front teeth.

I say “only”, but this still needs him to keep still with a drill inside his mouth and not bite the dentist or her to cut his tongue.

So far so good

After six visits, three teeth have their fissure sealant and one more visit remains.

Monty is friends with the dentist and is dancing to the music in the waiting room as he leaves for home.

Who could have imagined such a surprise at the dentist?

Ketamine, Memantine, D-Cycloserin, Magnesium, Fenobam and yet more as Glutamatergic Modulators in Autism (and Fragile X)

 

Much of this blog to date has been connected with aspects related to the neurotransmitter GABA.  It did get rather complicated, but at least for me, it has been highly rewarding. I have identified treatable dysfunctions in Monty, aged 10 with ASD, using Bumetanide and now Clonazepam.

It is also clear that a group of people with autism also benefit from treatment with R-baclofen, a potent GABA_B receptor agonist. R-baclofen/Arbaclofen and Arbaclofen Placarbil are not commercially available.  The commercially available drug Baclofen contains R-Baclofen and another substance that, in-effect, works to oppose it and so may be much less effective.

Based on the successful results of this investigation into GABA-related interventions, it would therefore make sense to look in detail at Glutamate, the other neurotransmitter that appears to be dysfunctional in many types of autism.

As with GABA dysfunctions, there are already are some existing treatments for glutamate dysfunctions.

While many researchers have concluded that glutamate is implicated in autism, some think, in effect, there is too much and some think there is too little.  Since we have learnt that in fact within “autism” are many discrete diseases, both groups of researchers might be right. 

In other types of neurological disorders glutamatergic modulators are an emerging therapy and there are many ongoing clinical trials.  Off-label, some of these therapies have been used for decades.  In autism there have been some trials over the years, but as seems to be often the case, they are not followed up to a final undisputed conclusion.  This may be about to change.

Yet again, the mineral Magnesium appears and there is yet another possible explanation for its apparent positive impact, in some cases of autism. 

I imagine that under the umbrella diagnosis of autism, there are those who have a GABA dysfunction and there are those that have a Glutamate dysfunction.  Just to complicate matters, if there is Serotonin dysfunction, this will affect both GABA and Glutamate.  So everything is inter-related and nothing is simple. Fortunately, in medicine, trial and error is a long trusted technique and “stumbled upon” is still a satisfactory explanation; we do not need to understand things 100%.

First we have to look at the terminology and in doing so we stumble upon a novel hypothesis as to what caused autism in the first place, which occurred to me today, but back in 2007 at the University of Mississippi.

Glutamate

Glutamate is the most abundant excitatory neurotransmitter. Glutamate is involved in cognitive functions like learning and memory in the brain.  Too much glutamate can be extremely bad for you and research shows it leads to neuronal death, mental retardation and indeed autism. 

So called Glutamate transporters remove glutamate from the extracellular space. In brain injury or disease, they can work in reverse, and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death;  this is called excitotoxicity.



So it is plausible that the root cause of the autism is actually a dysfunction of one of the glumate transporters.  The calcium ions are just the messenger.


There are 4 types of glutamate transporter. When there is a dysfunction the following is known to happen:-

·        Over activity of glutamate transporters may result in inadequate synaptic glutamate and may be involved in schizophrenia and other mental illnesses

·        During injury processes such as ischemia and traumatic brain injury, the action of glutamate transporters may fail, leading to toxic buildup of glutamate. 

·        Loss of the Na⁺-dependent glutamate transporter EAAT2 is suspected to be associated with neurodegenerative diseases such as Alzheimer's disease

Excessive glumate release

Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke, autism, some forms of intellectual disability, and diseases like Alzheimer's disease.

Epilepsy and Calcium Channels

Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization

Too much or too little Glutamate Activity?

Studies propose both hyper-and hypoglutamatergic ideologies for autism.

Hypothesis: Is infantile autism a hypoglutamatergic disorder? Relevance of glutamate – serotonin interactions for pharmacotherapy

The hyperglutamatergic hypothesis of autism

You may be thinking that somebody is clearly wrong here, but it is not so simple.  We will see later, when we get to the clever people at MIT, that in fact both views may be correct; in some people their autism is improved by inhibiting the specific receptor (mGluR5) and in other people by exciting the same receptor.

GABA & GAD

Glutamate also serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons. This reaction is catalyzed by glutamate decarboxylase (GAD), which is most abundant in the cerebellum and pancreas.

GAD is interesting in itself.  There are two types, GAD₆₇ and GAD₆₅
It appears that anti-GAD antibodies are the trigger that leads to diabetes.  Since the pancreas has abundant GAD, a direct immunological destruction occurs in the pancreas and the patients will have developed diabetes.

Diabetes

Both GAD₆₇ and GAD₆₅ are targets of autoantibodies in people who later develop type 1 diabetes or latent autoimmune diabetes. Injections with GAD₆₅ has been shown to preserve some insulin production for 30 months in humans with type 1 diabetes

Schizophrenia and bipolar disorder

Substantial dysregulation of GAD mRNA expression, coupled with down regulation of reelin, is observed in schizophrenia and bipolar disorder. The most pronounced down regulation of GAD67 was found in hippocampal stratum oriens layer in both disorders.

Parkinson disease

The bilateral delivery of GAD by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study

Cerebellar disorders

Intracerebellar administration of GAD autoantibodies to animals increase the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning. Epitope recognition contributes to cerebellar involvement

Stiff Person Syndrome

Anti-GAD antibodies are associated with Stiff-person syndrome but their causal role is not yet established.

We have seen before that comorbidities of autism can point us in the right direction and also that many mental health / neurological disorders are overlapping.
So is not a surprise that a GAD dysfunction also exists in autism:-

Decreased GAD67 mRNA levels incerebellar Purkinje cells in autism: pathophysiological implications

Decreased GAD65 mRNA levels inselect subpopulations of neurons in the cerebellar dentate nuclei in autism: anin situ hybridization study.

“This suggests a disturbance in the intrinsic cerebellar circuitry in the autism group potentially interfering with the synchronous firing of inferior olivary neurons, and the timing of Purkinje cell firing and inputs to the dentate nuclei. Disturbances in critical neural substrates within these key circuits could disrupt afferents to motor and/or cognitive cerebral association areas in the autistic brain likely contributing to the marked behavioral consequences characteristic of autism.

Both GAD isoforms have been shown to be affected in a variety of psychiatric and developmental disorders. GAD67 has been implicated in schizophrenia, bipolar disorder, major depression disorder, and autism.

In animal studies, GAD65 is strongly implicated in anxiety.

Clinical research indicates that discrete cerebellar lesions, in otherwise healthy children, cause behavioral and/or cognitive impairments. In autism, however, cerebellar pathology is likely acquired during critical developmental period(s) when the brain is capable of constructing alternate innervation patterns. It is thus possible that there is a “miswiring” of key circuits in the autistic cerebellum with a developmental basis persisting into adulthood”

We see again a form of self-destruction.  With arthritis the body destroys its joints and with diabetes, the pancreas is (partially) destroyed.

From the research it would appear that low levels of GAD67 and GAD65 played a critical role in the process that initiated the brain damage that led to autism.  Perhaps the low levels are the result of GAD antibodies.

GAD antibodies test as a predictor

There is a widely available of a GAD antibodies test.  Because diabetes is so common, it is also well researched.

GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

So now back to autism.  Now, I am thinking that maybe pregnant mothers might have high levels of GAD antibodies and this might be passed on to the developing fetus, potentially causing brain damage (autism) or perhaps diabetes later in life.  Well, somebody has already come to the same conclusion.

A pathogenetic model of autism involving Purkinje cell loss through anti-GAD antibodies

“Conclusions

Studies of serum GAD-Abs in autism are warranted but have not been done so far. Positive findings would stimulate the development of specific prenatal diagnostic markers and therapeutics that may involve maternal administration of immunosuppressants to prevent the development of

autism or intravenous immunoglobulins therapy in children with emerging autistic symptoms.”

This again points towards immunomodulation as a therapy, this time for the mother.  Such treatment, in mothers with high GAD-Abs (GAB antibodies) might lead to a reduction is in cases of autism and indeed diabetes (type 1).

In the case of children and adults with autism, treatment with GAD65 or GAD67 might be effective, or it might just be too late to do any good.  This would be worthy of study.

Glutamate receptors

Glutamate receptors are responsible for the glutamate-mediated excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
Glutamate receptors are implicated in a number of neurological conditions. Their central role in excitotoxicity and prevalence in the central nervous system has been linked or speculated to be linked to many neurodegenerative diseases, and several other conditions have been further linked to glutamate receptor gene mutations.

There are four types of glumate receptors.

The first three types are Ionotropic, and by definition, are ligand-gated nonselective cation channels that allow the flow of K⁺, Na⁺ and sometimes Ca²⁺ in response to glutamate binding.  Upon binding, the agonist will stimulate direct action of the central pore of the receptor, an ion channel, allowing ion flow and causing excitatory postsynaptic current (EPSC). This current is depolarizing and, if enough glutamate receptors are activated, may trigger an action potential in the postsynaptic neuron

NMDA receptor

Kainate receptor

AMPA receptor
 
The fourth type is:_
 

metabotropicglutamate receptors or mGluRs

These receptors are involved in Ca²⁺  and K⁺  ion channels and varying the concentration of Ca²⁺  and K⁺  

Glutamate binding to the extracellular region of an mGluR causes G proteins bound to the intracellular region to be phosphorylated, affecting multiple biochemical pathways and ion channels in the cell. Because of this, mGluRs can both increase or decrease the exitability of the postsynaptic cell, thereby causing a wide range of physiological effects.

 

Selected Conditions associated with Glumate Receptors (source Wikipedia)

Attention deficit hyperactivity disorder (ADHD)

In 2006 the glutamate receptor subunit gene GRIN2B (responsible for key functions in memory and learning) was associated with ADHD.  This followed earlier studies showing a link between glutamate modulation and hyperactivity.

Further mutations to four different metabotropic glutamate receptor genes were identified in a study of 1013 paediatric ADHD patients compared to 4105 non-ADHD controls, replicated in a subsequent study of 2500 more patients. Deletions and duplications affected GRM1, GRM5, GRM7 and GRM8. The study concluded that "CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9)", "over 200 genes interacting with glutamate receptors were collectively affected by CNVs", "major hubs of the (affected genes') network include TNIK50, GNAQ51, and CALM", and "the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD".


In 2012 UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism. The findings suggest agonizing mGluRs in patients with ADHD or certain forms of autism and antagonizing the targets in other forms of autism

 

Although the precise molecular basis of the interaction remains to be determined, the data show unambiguously that mGluR5 and FMRP act as an opponent pair in several functional contexts, and support the theory that many CNS symptoms in fragile X are accounted for by unbalanced activation of Gp1 mGluRs. These findings have major therapeutic implications for fragile X syndrome and autism.

Autism

The etiology of autism may include excessive glutaminergic mechanisms.
A link between glutamate receptors and autism was also identified via the structural protein ProSAP1/SHANK2 and potentially ProSAP2/SHANK3. The study authors concluded that the study "illustrates the significant role glutamatergic systems play in autism" and "By comparing the data on ProSAP1/Shank2^−/− mutants with ProSAP2/Shank3αβ^−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

Seizures

Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.  Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in preventing convulsions.

 Current and Future interventions

 

The possible interventions that follow from what we have learnt would appear to be:-

1.     Targeting NMDA glutamate receptor function

2.     Targeting mGluRs (metabotropic glutamate receptors)

3.     Targeting glutamate transporters

4.     GAD therapy

There would seem to be four possible areas of intervention.  The first one is to target the NMDA glutamate receptors using existing drugs and other three are cleverer, but only possible using experimental drugs. 

Very few pharmacological tools are currently available to investigate glumate transporter (EAAT) function and to then consider these transporters  as therapeutic targets, but even that is beginning to change.  Here is a Glutamate Transporter Inhibitor:-

 

Neuroprotective Effects of the Novel Glutamate TransporterInhibitor (_)-3-Hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylicAcid, Which Preferentially Inhibits Reverse Transport (Glutamate Release)Compared with Glutamate Reuptake

 

I do like the idea of targeting GAD. It is possible to do it and the idea is being developed by a company called Neurologix as a treatment for Parkinson’s Disease (PD).  There are also working on epilepsy treatment.

 

"Neurologix's gene therapy approach to PD aims to reset the overactive brain cells to inhibit electrical activity and return brain network activity to more normal levels. The strategy involves restoring GABA and thus improving the patient's motor control by using an AAV vector (a disabled, non-pathogenic virus) to deliver the GAD gene back into the STN (subthalamic nucleus). Increasing GAD causes more GABA to be synthesized, thus helping to calm the STN over-activity."

 

They are calling it gene therapy for PD; I would call it GAD therapy.  I think GAD therapy might well be effective in some types of autism.

 

mGluRs

 

Targeting mGluRs is very much associated with a researcher called Mark Bear at MIT.  We came across him earlier in this blog, since he is also the man behind Arbaclofen, at Seaside Therapeutics.

 

This research is very recent and is linked to Fragile X.  Here is a PhD thesis written in 2013 by one of Mark Bear’s students, which seems to sum things up.

 

Contributions of metabotropic glutamate receptors to the Pathophysiology of Autism

 

If you can follow my blog, you can definitely follow his thesis.  In effect, what he is saying is that errors in synaptic protein synthesis are behind several types of autism and that these errors can be corrected using either positive or negative stimulators of the receptor mGluR5.  It is clear that at Bear Lab, they view all autisms as part of a family, rather than discrete disorders.

 

 

This would imply that positive allosteric modulators and negative allosteric modulators of MGluR5 are potentially effective autism treatments.  Another name would be MGluR5 agonist/antagonist.  Such drugs are already under study in both autism and other conditions.  Here are two examples.

 

Potentiating mGluR5 function witha positive allosteric modulator enhances adaptive learning.

 

Safety, Tolerability and Anti-Dyskinetic Efficacy of Dipraglurant, a Novel mGluR5 Negative Allosteric Modulator  in Parkinson's Disease Patients with Levodopa-Induced Dyskinesia

 

Seaside Therapeutics, Roche and Novartis have each developed therapeutic compounds targeting the mGluR5 pathway.


Roche is developing RG7090, an inhibitor of mGluR5 that is currently in clinical trials. CTEP is a mouse version of RG7090.  One dose of CTEP, which can be taken orally, deactivates most mGLuR5 receptors in the brain for about 48 hours.

A single dose of CTEP is enough to reverse the same features of fragile X syndrome — such as an overproduction of proteins in the brain and susceptibility to seizures — as those treated by previous mGLuR5 inhibitors. It also corrects a process that allows neurons to change the strength of their connections in response to learning.

It took four weeks of continued treatment to see improvements in the behavioral features of the syndrome, including sensory sensitivities and problems with learning and memory.

 

Fenobam

 

Fenobam is an existing inhibitor of mGluR5, developed in the 1970s.  It was trialed in Fragile X in 2009 with good results using just a single dose.

 

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

 

“In summary, this trial did not find major safety concerns to a single administration of fenobam in FXS, and suggested that clinical improvements in behaviour and PPI may be seen even after a single dose. This would indicate that placebo controlled trials of fenobam and other mGluR5 antagonists involving longer term treatment of individuals with FXS should be considered to investigate whether rescue of the FXS phenotype observed in animal models can be extended to humans.”

Fenobam is being trialed byWashington University, but not for autism.

 

Current interventions

 

The current interventions are mainly NDMA receptor antagonists and are based on that trusted medical approach called trial and error, rather than the Bear Lab approach .  The drugs are:-

·        Ketamine

·        Memantine,

·        D-Cycloserine

·        Magnesium

·        Fenobam (mGluR5 inhibitor – see above, not FDA approved)

 

Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: 

1. Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate
2. noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites
3. Uncompetitive antagonists, which block the ion channel by binding to a site within it
4. glycine antagonists, which bind to and block the glycine site

Ketamine is a non-competitive antagonist.  It has recently been in the headlines for having a remarkable effect in some cases of depression.

In large doses it is used as an anaesthetic particularly in children and pet animals.  It is also used as a recreational drug “Special K”, which is why it is a controlled substance.

In small doses the intra-nasal route is favoured.  In effect the vial of ketamine normally administered by injection is diluted with a saline solution and put in a standard metered dose nasal spray.  It is also possible to make eye drops the same way.  The nasal/eye route is effective since the drug can enter the bloodstream without the need for an injection or a very ineffective oral tablet.

A study is underway in Cincinnati to test intranasal ketamine on adults with autism.

Ketamine Use in Autism Spectrum Disorders

Dr. Logan Wink, Cincinnati Children's Hospital

Start Date: 11/2013

In a human clinical trial with 24 adults with Autism, researchers at the Cincinnati Children’s Hospital will conduct a pilot double-blind placebo controlled study of intranasal ketamine in adults with ASD using novel quantitative outcome measures of social and communication impairment.

Ketamine has a unique drug profile clearly differentiated from other glutamatergic modulators (drugs that support the glutamate receptors) studied in ASD to date. This profile, coupled with ketamine’s long safety track record and novel intranasal (IN) delivery system, make ketamine worthy of drug investigation for treatment of the core features of ASD. As a generically available inexpensive drug, ketamine holds significant promise to widely treat the core social and communication impairments that are the hallmark of ASD. The results of this study, if positive, would support the use of a drug with a demonstrated safety profile that is cost-effective to use.

If this pilot project demonstrates efficacy and tolerability of IN ketamine, the next steps will include the following. 1) Design and obtain funding for a large phase II placebo controlled trial of ketamine in adults with ASD. 2) Design a pilot study of ketamine in children with ASD. 3) Publish the data on the pilot study for other researchers and clinicians to use to support patients with ASD.

Memantine is an uncompetitive agonist.  It has a modest effect in moderate-to-severe Alzheimer's disease.  It has been around for a long time, having been first synthesized in 1968.

There are two other Alzheimer’s drugs that seem to be helpful in some types of autism.  They are Donepezil (Aricept) and  Galantamine   They are both centrally acting reversible acetylcholinesterase inhibitors.  So they work in an entirely different way to Memantine.

There have been several trials of Memantine in autism over the years.  Recently the producer, Forest Laboratories have been intensive trials to show its effectiveness and safety in childhood autism.

In 2007 Michael Chez carried out a study:- 

Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability

                             

Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. To generate a clinician-derived Clinical Global Impression Improvement score for language, behavior, and self-stimulatory behaviors, the primary author observed the subjects and questioned their caretakers within 4 to 8 weeks of the initiation of therapy. Chronic maintenance therapy with the drug was continued if there were no negative side effects. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects.

 Autism speaks have funded studies:-

 

A Placebo Controlled Trial of Memantine in Children and Adolescents with Autism 

A multi-site double-blind placebo-controlled trial of memantine vs. placebo inchildren with autism

Even the Iranians have been trialing it, but as usual as an adjunct therapy.

Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized,double-blind, placebo-controlled trial

Forest Laboratories have a series of trials underway of Memantine in autism

The full list is here

It appears that Forest have terminated what was to be a two year study.  Here is a blog post by one of the parents:-

 

D-Cycloserine is a glycine antagonist.  Its main use is as an antibiotic for treating drug resistant TB.  It is also used to treat drug addiction and social anxiety disorder.

It has been investigated in both mouse models of autism and in humans.

A Pilot Study of d-Cycloserine in Subjects With Autistic Disorder 

Abstract

OBJECTIVE: The authors assessed the effects of d-cycloserine on the core symptom of social impairment in subjects with autism. METHOD: Following a 2-week, single-blind placebo lead-in phase, drug-free subjects with autistic disorder were administered three different doses of d-cycloserine during each of three 2-week periods. Measures used for subject ratings included the Clinical Global Impression (CGI) scale and Aberrant Behavior Checklist. RESULTS: Significant improvement was found on the CGI and social withdrawal subscale of the Aberrant Behavior Checklist. d-Cycloserine was well tolerated at most of the doses used in this study. CONCLUSIONS: In this pilot study, d-cycloserine treatment resulted in significant improvement in social withdrawal. Further controlled studies of d-cycloserine in autism appear warranted.

Autistic-likesocial behaviour in Shank2-mutant mice improved by restoring NMDA receptor function

Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank22/2 mice.

These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank22/2 mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.

 

Magnesium

Magnesium is an uncompetitive NMDA channel blocker.  As you can see below on the diagram of the NMDA receptor site  (source Wikipedia)

 

1. Cell membrane
2. Channel blocked by Mg2+ at the block site (3)
3. Block site by Mg2+
4. Hallucinogen compounds binding site
5. Binding site for Zn2+
6. Binding site for agonists(glutamate) and/or antagonist ligands(APV)
7. Glycosilation sites
8. Proton biding sites
9. Glycine binding sites
10. Polyamines binding site
11. Extracellular space
12. Intracellular space

Magnesium seems to have a therapeutic effect in some types of autism.  There are several possible reasons why this might be and these have been covered in earlier posts.  The idea of using magnesium to block dysfunctional NMDA receptors is intriguing.  It is clear from the graphic that the receptor has evolved with this specifically in mind.

There are two simple ways to raise the concentration of magnesium, one is orally and the other is trans-dermally.  A problem with the oral route is that magnesium tends to upset the stomach and that is why it is used as laxative.

The clever transdermal route is take a bath in Epsom salts (MgSO₄) this will raise the level of magnesium (also sulphate).

Many people take such baths to feel better and look better, but be aware they also will reduce your blood pressure.  Some celebrities claim to take a daily bath in Epsom salts.

While some parents report that their child with ASD has behavioral improvements after an Epsom salt bath, in Monty, aged 10 with ASD, the reverse is true.  It does not make him calm, it agitates him.

Since it is cheap and widely available, an Epsom salt bath is not a bad thing to try.  Maybe it helps and maybe it will not; you will only know by trying.

 

Conclusion

Most likely in some subtypes of autism there is too much (hyper-function) glutamate activity, in some subtypes there is too little (hypo-function) and in other sub-types glutamate function is not impaired at all.  This is again saying that sub-types are different diseases.

For the time being, the only therapy would be one of trial and error with existing drugs.

Intranasal ketamine therapy is intriguing, but this might be hard to get hold of unless you are in a clinical trial, or your neighbour is a vet.

 “I have had very good success using ketamine eye drops in varying dilutions from 1:100 down to 1:5. Some of the responses have been quite remarkable. I also make ketamine nasal spray 1:25 and 1:10 and monitor its use because of a slight potential for abuse.”   Dr Jay Goldstein, treating various neurological disorders

Memantine has now been trialed in over 1,000 children.  If it was highly effective in a large percentage of people, I think we would have heard about it.  It looks to be the "wrong" Alzheimer's drug , the other two, Donepezil and Galantamine seem more beneficial for ASD.


One long-existing mGluR5 inhibitor, Fenebam, has already been trialed on people with Fragile X.  Until other drugs are developed, I wonder why this drug has been forgotten.

In the medium term, the new mGluR5 positive and negative modulators look like they may be able to address core defects in some sub-types of autism.  This would be a case where hard science and medicine really did work as they should (i.e. together).  I would put my money on this being the most effective Glutamate-related therapy. 

I personally like to look for the route cause, as far back up the chain of events as possible, to where the trouble began, and that might point to GAD therapy, but that is far in the future.