Lessons from the Autistic Mouse

 

One surprising observation from reading the research on autism is how many times I have come across scientists making a mouse autistic and then showing how this can be reversed.

The important point is that the things the scientists did to the mouse (or its mother) are generally totally unrelated.  The only thing in common is the resulting mouse has “autistic behaviour”.

We can conclude that “autism” can be caused by entirely different events/disorders;  just like a head ache can be.

It would be correct to think of autism as a symptom, not a disease.

Perhaps, put a little clearer:-

• Autism is just a symptom of an underlying neurological disorder.  There are numerous such disorders, each with their own underlying pathology; some of these pathologies may overlap.  Treating the underlying pathology will moderate the symptoms of autism.

• Do not treat autism.  Treat the underlying pathology.

• A treatment that works in one person, with the symptoms of autism, may be completely ineffective in another.

• All treatments that are genuinely effective, in even the smallest group of children, should be carefully documented and shared publicly. Steps should be taken to look for biomarkers associated with each group.   

So, it is fundamental to think of autism as a symptom rather than a disease.

If researchers think of autism as a disease, it will likely remain incurable.  Granted, there is much more talk about autisms, sub-types and phenotypes, but this all goes out the window, so to speak, when it comes to doing clinical trials.

I am reading about a series of autism trials by Forest Laboratories of the US, using an old drug called Memantine.    I was shocked to see that they are trialing this drug in 118 locations around the world, on 906 children

An Open-Label Safety Study of Memantine in Pediatric Patients with Autism, Asperger's Disorder, or Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) 

Autism trials are usually tiny.  Conducting a trial on nearly a thousand kids is very expensive.  You would not undertake this kind of expense, unless you had a pretty good reason to think the drug was effective.

This trial is actually a safety study, in parallel there are a whole series of other studies.

Unfortunately, by trialing the drug on almost any kid, with any kind of autistic feature (Autism, Asperger’s, PDD-NOS), the important lesson from the mice has been completely lost.

While I really wish Forest Laboratories success, I suspect their trial will show that while Memantine is safe, it is not effective.

Over the years, there have been many anecdotal reports of the effectiveness of Memantine in some cases of autism.  Memantine is a drug that acts on the glutamatergic system by blocking NMDA receptors.  This will be explained in some detail in the next post “Ketamine, Memantine, D-Cycloserine and even Magnesium as Glutamatergic Modulators in Autism”.

Conclusion

You might think that much of the above should be common sense; sadly it is not.

PolyPill for Autism - Current Version

The objective was to identify the most effective drugs to treat Classic early-onset autism, having biomarkers of elevated serotonin, cholesterol, thyroid FT3/4 and growth factor IGF-1.  Except for the TRH drug, these drugs are all generic and very cheap.  The total cost per day is about EUR 1 ($1.4).

The dosage is based on a 10 year old child weighing 33kg / 73lbs

The TRH and Clonazepam doses are tiny.

According to the European Medicines Agency (EMA), most countries have an arrangement whereby patients can apply for access to drugs for off-label use, usually based on experimental evidence or clinical trials.  If you use these drugs, it would be helpful to collect data on the effect, so that it can later be used by the EMA to evaluate the Autism Polypill.  You can send me the data or case reports.

Since most doctors continue to regard autism as untreatable, you will have to be proactive, if you want a drug to treat your child. 

True Self

I could have given this post and the above graphic a fancy name like "Psycho-neurobiological model of autism", but True Self seems more appropriate.

If you have ever read a book on autism by a psychologist, it is worlds away from the books by the scientific boffins.  In reality, the psychologists have a simpler job, since they do not have to prove their theories with biological data.

One interesting observation from psychology is the concept that the human body has two parallel control mechanisms, the nervous system and the hormone system.  The nervous system mediates immediate changes, while the hormonal system sets the background changes.

When it comes to fear and stress, there are measurable hormonal changes.  Using willpower or even singing, you can make your self feel better and make a measurable change in the hormone levels.  We saw this earlier with the example of singing lowering the stress hormone cortisol, as measured in saliva.

This NIKE (Just do it!) effect means that you can directly influence your own hormones.  By inference, if you have a hormone imbalance, as seems to be the case on some types of autism, you have some powers to modulate it yourself.  You could think of it as willpower, or mind over matter. 

I suggest that even instincts may fall into this category.  Just as soldiers are taught to react instinctively, without pausing for thought, it should be possible to teach young children to develop their instincts.  The apparent lack of gross motor skills in kids with ASD can often be overcome with practice and repetition (the foundations of ABA);  in effect you are teaching the child what is instinctive in other kids.  If you through a ball at a younger kid with autism, he does not react and will let it hit him.  He does not know what to do and he lacks the instinct to either get out of the way, or to catch it.

As part of a good ABA programme a lot of time is spent practicing both gross motor skills (ball play, jumping, dancing etc) and fine motor skills.  Then you have these skills, without the need to consciously think about them.

People do ask why ABA seems to work so well for some children, is it the child? is it the therapist? it is just the sheer amount of it that matters?  They tend not to wonder what the ABA is actually doing inside the child's head.

It is relevant to this blog, which is all about the biology of the brain.  We have a pretty good idea of some of things that are dysfunctional in autism and how some emerging drug interventions work.  But at the same time, there is this behavioral intervention that seems able to overcome some of these biological deficits.

The NIKE effect (Just do it) and the AVIS effect (We try harder) are extremely potent.  In reality, they are very much part of the body's nervous control system.  In some cases this training is so powerful that instead of being derailed by interference from ion channels and oxidative stress, all that matters is completing the task.

Some typical people's headaches are also caused by ion channel dysfunction; when it happens they might call in sick.  Another type of person is more driven, the fact they have some other obligations is more important than their headache, so they just press on.



The Faucet/Tap/Valve

A conventional faucet/tap might look like this old one on the left.

A so-called "in line valve" has a pipe on both ends and as you turn it, you gradually reduce the flow to zero

If you make a technical drawing involving a valve, there are various special symbols, but they generally look like this.  Sometimes if the valve is closed it would be solid black.






Why does drug intention in autism sometimes stop working ?

We have seen in this blog that several apparently different, but interconnected, conditions seem to mediate autism, at least in some people:-

• Oxidative stress
• Neuroinflammation
• Channelopathies
• Hormonal dysfunction
• Immune system "over-activation"

So if you now look again at the True Self graphic

Oxidative stress, if present, will manifest itself as stereotypy and in the graphic it will close the valve a little blocking the true self.  In hard science, the oxidative stress will also reduce the level of the thyroid hormone T3 in the brain.  We saw this in research from Harvard that showed that the oxidative stress reduces the level of the enzyme D2 that converts the pro-hormone T4 into T3.  So both the blue valve and the green valve close.

In similar fashion both neuro-inflammation and channelopathies affect both the nervous system and the hormonal system. 

This might explain the fact that sleeping patterns, appetite, emotions, empathy, self-confidence are all sometimes impaired in autism.  To some extent, these impairments seem to be reversible.

In the only real case of autism that I have to contend with, the most important factor seems to be, the sometimes over-activated, immune system.  I am presuming it is just affecting the nervous system.  In this case, the blue valve to the left can shut completely; the Observable Self is then a totally different person to the True Self.  It also means that even though the other valves upstream may be wide open, it is all to no avail.

So when my autism drugs "stopped working" it was because further down stream there was an insurmountable problem.  Even NIKE and Avis had little effect.   

In the children for whom none of these drugs show any effect, I suspect either the immune system is involved, or in their type of autism, there are other additional factors at play.


A Note on ABA


ABA (Applied Behavioral Analysis) is not the subject of this blog, but it would be more than worthy.  When well implemented, ABA is a powerful resource and not only for small children.  The general public perception of ABA rather misses the point, it is actually more a philosophy applicable life-long.

We once had an excellent young ABA consultant trained at the New England Centre for Children, in Massachusetts.  I was surprised to hear from her about the support still being given to older adults; the adult and their buddy (ABA assistant) would even go on short trips, like to Las Vegas.

We are now using ABA to develop conversational skills.  An example is giving Monty, aged 10 with ASD, the task in break time at school, to go and initiate five conversations with the potential reward of his favourite candy.  This might sound very staged, but he goes around the school looking for kids to talk to, some of whom he has never spoken to before, initiates the conversation, looks over his shoulder to check his assistant has noticed, plays a bit and then finds someone else to talk to.  He did not take the easy option and just find the nearest five kids and say "Hi, how are you".  I was surprised how well this worked.

Later you can fade the reinforcer, so that he works for praise and not candy.  You can also gradually increase the target of five conversations.  You can then also extend the requirement to have more stages to and fro, in the conversation.  It may sound very odd to do this, but the end result will be learning to make social conversation, which would be natural in other kids.  

What people do not realize is just how much ABA is needed and that it is not just like having a music lesson, it is more like a religion.  If everyone who interacts with the child consistently applies the principles, much can be achieved.  If ABA is just a lesson the child goes to and then comes home, it is not a surprise that very much less is achieved.

If you talk to the parent of a child who has persevered with ABA for years, you will see just how committed they became.  If you prefer sport as an analogy, it is just like a would-be professional tennis player, who practices every day from the early hours.  It is an obsession, but if you want to compete at a high level, you just have to do it.

Where we live there is no ABA school, but there is a Novak Djokovic tennis academy, in fact they came to visit Monty's school last week.  I think Novak would definitely understand the NIKE and Avis effects, he probably would not think ABA was odd at all.









 

Clonazepam Dosage and Effectiveness in Autism

Much research is based on experiments with mice rather than humans, for obvious reasons.  This was the case with Dr Catterall’s recent successful trials of a long established drug called Clonazepam, in two mouse models of autism.

Well, it turns out that his findings are applicable to humans.

With a dosage of around 1mcg/kg (that is micrograms per kilo) twice a day, the same kind of positive behavioural/cognitive changes Catterall found in mice are indeed evident in some humans.

The question remains as to the long term effect of using this drug; in very much higher doses, there are negative consequences.

Comparison with dosage for other conditions

·        As a treatment for seizures, the maximum dosage in children for 0.2 mg/kg/day

·        As a treatment for panic/anxiety the typical adult dose is 1mg with maximum of 4 mg

·        For bipolar disorder in adults the maximum dose is a hefty 20 mg

Clonazepam use in the above conditions is associated with both tolerance (gradually needing a higher dosage to maintain effectiveness) and being habit forming (addictive).

The autism dose appears to be just one hundredth of the maximum pediatric anti-seizure dose and is perhaps too low to cause problems. 

 

Increase in Serotonin

Not only does Clonazepam affect the neurotransmitter GABA, but it has a known secondary effect on serotonin, the “happy hormone”, which appears to be low in the autistic brain.

In the US the trade name is Klonopin and it appears to be called “K-pin” among those who abuse it, for the happy effect.

In most of the rest of the world it is called Rivotril.

 

Just how dangerous is Danger Mouse?  (in tiny doses)

Nobody knows.

For the science, click below:-

Channelopathies in Autism - Treating Nav1.1 with Clonazepan
 

 

 

Channelopathies in Autism - Treating Nav1.1 with Clonazepan

In this post we look at another existing drug that research shows may be effective in treating core symptoms of autism.  The drug, Clonazepam, is inexpensive and is already used in larger doses to treat anxiety in autism.

 

You make have seen this Venn diagram before, it is one of those graphics I like to produce to make things easier to understand, both for you and for me.

In our quest to treat autism we first need to understand the disease as much as possible.  By far the most complex of the four main areas is the dysfunction of the ion channels and transporters in the brain, the so-called channelopathies.  Ion channels were only discovered relatively recently and science's understanding of them is still evolving.

Here is very useful layperson’s summary:- 

Autism-Linked Variations in Ion Channel Genes Increase Brain Excitability

 

"Neuronal communication guides virtually all aspects of brain development. To better understand Autism Spectrum Disorders (ASD), scientists are searching for autism-linked genes that regulate neuronal activity. Some of these genes encode ion channels, whose activation determines whether a neuron will fire a signal. Variations in ion channels influence neuronal survival, differentiation, migration, outgrowth, and synapse formation.

Ion channels are critical for shaping neuronal excitability. Neurons encode information using electrical signals derived from ion channels. At rest, each neuron has a negative charge. When a neuron receives signals from other neurons via synapses, ion channels open and the neuronal charge becomes either more positive or negative, depending on the type of ion. Once the charge of a neuron rises to a certain threshold, the neuron “fires” a signal to other neurons in a process called emitting an “action potential.”

Think of this process like the boiling of a teapot. The bottom of the teapot receives heat from the burners of the stove, much like how dendrites of a neuron receive synaptic signals. This heat boils the water in the teapot, converting it into steam, just as neurons convert synaptic signals into electrical charges. As the pressure builds, steam escapes through the spout, letting off a loud whistle. Likewise, once a neuron builds up enough positive charge, it sends a fast action potential down its axon to the next neuron.

Positive ion channels boost neuronal excitability by creating a more positive charge. However, the balance of neuronal excitability is crucial. Too much excitation leads to seizures and epilepsy, whereas too little prevents circuits from firing. Individuals with autism frequently also have epilepsy, suggesting that their brains are overexcited.

ASD-linked mutations in genes for calcium (Ca2+), sodium (Na+), and potassium (K+) ion channels enhance brain excitability, although the exact mechanisms are not well understood. Known ASD-associated mutations occur in the genes CACNA1C, CACNA1F, CACNA1G, and CACNA1H, which encode the L-type calcium channels Cav1.2 and Cav1.4 and the T-type calcium channels Cav3.1 and Cav3.2, respectively; the sodium channel genes SCN1A and SCN2A, which encode the channels Nav1.1 and Nav1.2, respectively; and the potassium channel genes KCNMA1 and KCNJ10, which encode the channels BKCa and Kir4.1, respectively.

Variations in ion channel genes are likely to affect a myriad of brain functions. Ion channels may even provide a link between genetics and the environment because environmental factors like mercury increase calcium signaling. The broad role of ion channels may help explain why ASD is so often accompanied by other neurological complications like sleep problems and epilepsy."

Catherine Croft Swanwick, Ph.D.

In this blog I have so far covered a potassium channelopathy and a chloride channelopathy.  From my own research, I already know there are more.

In today’s post we will look at some very extensive research by  Dr Catterall, who seems to be the world’s expert on a specific sodium ion channel called Na_V1.1.  Catterall has shown how it is implicated in two models of autism and it can be effectively treated/reversed using existing drugs.

Dravet’s syndrome

Dravet’s syndrome is a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit and autism-spectrum behaviours. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviours in Dravet’s syndrome are poorly understood.  It is known that a dysfunction of the gene, SCN1A,  that encodes encoding voltage-gated sodium channel Na_V1.1 causes Dravet’s syndrome. 

Experiment Number One

In the first paper, Catterall used mice with a deficiency of the SCN1A gene to become his Dravets/autistic test examples.

The mice exhibited hyperactivity, stereotyped behaviours, social interaction deficits and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odours and social odours are aversive.  In effect he made autistic mice.

He goes on to explain that the behavioral deficit is mediated via impairments in GABAergic neurotransmission.  He tell us that treatment with low-dose clonazepam, a positive allosteric modulator of GABA_A receptors, completely rescued the abnormal social behaviours and deficits in fear memory in the mouse model.  

Autistic-like behaviour in Scn1a+/−mice and rescue by enhanced GABA-mediated neurotransmission

"Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA_A receptors, completely rescued the abnormal social behaviours and deficits in fear memory in the mouse model of Dravet’s syndrome, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for Na_V1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet’s syndrome."

Experiment number two

In a recent experiment, Catterall used a standard mouse model of autism called the BTBR mouse.  This is essential a specially bred mouse that exhibits very many traits of autism.  Nobody has purposefully interfered with its SCN1A genes or Na_V1.1 ion channels.

Enhancement of Inhibitory Neurotransmission by GABAA Receptors Having a2,3-Subunits ameliorates Behavioral Deficits in a Mouse Model of Autism

 

The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit specific—the α_2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α₁-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and α_2,3-subunit-selective positive GABA_A receptor modulation may be an effective treatment

In this study, Catterall repeated his use of low-dose clonazepam to try to “cure” the autistic mouse.  He not only was able to reduce the autistic deficits, but he was able to make cognitive improvements.  In effect he made the mice less autistic and smarter.

The following excepts from his paper are quite technical and you may wish to skip past them.

Increased GABAergic Inhibitory Neurotransmission in Response to Benzodiazepines

 

"Attempts to reverse autistic-like traits by rebalancing the ratio of excitatory to inhibitory neurotransmission through pharmacological treatments that reduce excitatory neurotransmission have met with only partial success because of their limited efficacy and unwanted side effects in control groups. 

The increased GABAergic signaling after treatment with clonazepam led to a decrease in frequency of spontaneous EPSCs (Figures 1G and 1H), without change in amplitude in BTBR hippocampal slices (Figure S1D). Interestingly, the frequency of spontaneous EPSC was also decreased by clonazepam (Figure S1K), without change in amplitude (Figure S1L) in C57BL/6J slices. 

These data support the idea that low-dose clonazepam can reverse the underlying deficit in spontaneous GABAergic inhibitory neurotransmission in BTBR mice."

 

Improvement of Social Interaction by Treatment with Clonazepam

 

"To test the behavioral effects of enhancing inhibitory neurotransmission in BTBR mice, we injected low nonsedating/nonanxiolytic doses of clonazepam intraperitoneally 30 min prior to behavioral tests. In the three-chamber social interaction test, acute clonazepam treatment had no effect on social  interactions of C57BL/6J mice (Figures 2A and S2A) but increased social interactions in BTBR, with a maximal effect at 0.05 mg/kg (Figures 2B and S2B) and no sedation (Figure S2H). Measurements of the time of interaction of the test mouse with a stranger mouse versus a novel object during three-chamber tests showed that the C57BL/6J mice are unaffected by any of the test doses (Figure 2C), whereas improvement of the social deficit in BTBR mice by clonazepam is strikingly dose dependent (Figure 2D). Interestingly, the improved social interactions in BTBR mice were lost at higher doses of clonazepam (Figures 2B and 2D). Other behaviors in BTBR mice were also rescued by low-dose clonazepam. In the open-field test, a single injection of 0.05 mg/kg clonazepam significantly reduced hyperactivity, measured as the total distance moved (Figure 2E), and stereotyped circling behavior, measured as the number of 360_ rotations (Figure 2F).

In contrast, these behaviors in C57BL/6J mice were unaffected by low-dose clonazepam. These low doses of clonazepam had little effect on anxiety-like behaviors of C57BL/6J mice, such as avoidance of the center of an open field or the open arms of an elevated plus maze (Figures 2G and 2H). However, compared to C57BL/6J, BTBR mice visited the center in the open field significantly more frequently and spent more time in open arms during the elevated plus-maze test under control conditions, as if they were less anxious than C57BL/6J mice, and these indicators of abnormally low anxiety in BTBR mice were changed toward the values for C57BL/6J mice after treatment with 0.05 mg/kg clonazepam (Figures 2G and 2H) without sedation (Figure S2I).

 

Amelioration of Cognitive Deficits by Treatment with Clonazepam

 

 

 

"Cognitive problems are often associated with ASD and BTBR mice are known to have impaired fear memory. To test the effects of low dose clonazepam on cognitive deficits, we performed context dependent fear conditioning after treatment with increasing doses of clonazepam in both BTBR and C57BL/6J mice (Figures 3A and 3B). Short-term (30 min) and long-term (24 hr) memory performance in fear conditioning to the spatial context in BTBR mice were improved by treatment with 0.05 mg/kg clonazepam, but no significant effects were observed after treatment with 0.0125 mg/kg or 0.1 mg/kg clonazepam (Figures 3B and S3B). In contrast, no cognitive changes were observed in C57BL/6J mice at any dose (Figures 3A and S3A)."

 

Rescue by a2,a3-Specific Positive Allosteric Modulators of GABAA Receptors

 

"Diversity of GABA receptor function is conferred by more than 20 different subunits, and receptors with different a subunits play distinct roles in the physiological and pharmacological actions of GABA and benzodiazepines."

"These results indicate that different subtypes of GABAA receptors may have opposite roles in social behavior, with activation of GABAA receptors containing a2,3 subunits favoring and activation of GABAA receptors with a1 subunits reducing social interaction, respectively."

"Altogether, these experiments show that treatment with an a2,3-selective positive allosteric modulator of GABAA receptors is sufficient to rescue autistic-like behaviors and cognitive deficit in both a monogenic model of autism-spectrum disorder and the BTBR mouse model of idiopathic autism." 

"Subunit-selective GABAA receptor modulators may also have an important effect on cognitive behaviors."

"The bell-shaped dose-response curves observed for both L-838,417 and clonazepam may explain why high-dose benzodiazepine treatment for prevention of anxiety and seizures has not been reported to improve autistic traits in ASD patients."

 

Discussion

"Our results on mouse models of autism support the hypothesis that social and cognitive deficits in ASDs may be caused by an increased ratio of excitatory to inhibitory synaptic transmission." 

"Therapeutic approaches to treat autistic traits in animal studies or in clinical trials have primarily focused on reducing excitatory neurotransmission in glutamatergic synapses to rebalance E/I ratio in autistic brain.  However, autistic-like behaviors in ASD mouse models are only partially reversed by drugs that inhibit excitatory neurotransmission, and these drugs also have unwanted side effects on wild type mice. To overcome these drawbacks, we focused on the opposing side, the GABAergic inhibitory transmission in autistic brain. Our results highlight the potential for therapy of autistic like behaviors and cognitive deficit in ASD by low-dose treatment with subunit-selective benzodiazepines and other positive allosteric modulators of GABAA receptors. At low doses that do not induce sedative or anxiolytic effects, we found that clonazepam, clobazam, and L-838,417 all improved autistic-like behaviors and cognitive deficit in BTBR mice, supporting the hypothesis that a2,3-subunit-selective up regulation of GABAergic neurotransmission could be an effective treatment for these core features of autism."

"Consistent with this view, Astra-Zeneca and the National Institutes of Health have initiated clinical trials of the a2,3-selective positive allosteric modulator of GABAA receptors, AZD7325, for efficacy in autism."

 

Experiment number three

Experiment number three is of course to test Dr Catterall’s idea about Clonazepam on humans.  This has not yet been done, although a trial is planned with a similar drug AZD7325.

He suggests trialing a low dose of clonazepam, but it is not clear exactly how low. There is mention of 10% of the normal dose. In large doses, clonazepam is already prescribed in autism to reduce anxiety, particularly in the US.  At even larger doses, clonazepam is used to treat seizures; given about 30% of people with autism also have seizures, it would be fair to assume that some of those are also prescribed clonazepam.

The downside is that clonazepam is a benzodiazepine, and this class of drug is habit forming.  In extremely low doses, perhaps this will not be a problem.  For anxiety, plenty of people have been prescribed it for 10+ years; the problem is they cannot stop taking it.

The pharmacological property of clonazepam is modulation of the GABA_A receptor; based on the mice, the effect is extremely dose dependent.  The wrong dose gives no beneficial effect.  Bumetanide, which is affecting GABA in a very similar way to make it inhibitory rather than excitory, seems to work like an on/off switch.  A low dose is ineffective, the correct dose works and a larger dose works just the same.

The optimal dose of clonazepam will be hard to find, too little does not work and neither does too much.  So for the time being it is rather trial and error.

By my calculations, a good place to start would be 0.8 Mcg (micrograms) per Kg per day and then titrate upwards gradually increasing the frequency and size of the doses.

The drug has a half-life that varies from person to person; the average is 30 hours but can vary between 18 and 50 hours.  This means that one child might need nearly 3 times as much as another, of similar weight.

To be an effective treatment the concentration of clonazepam would have to be maintained within the effective range.  This would need some clever maths, and might result in 3 unequal daily doses, and that during sleep the concentration  might be above range, and during daytime it be held in range with one or two smaller top-up doses.  

If you get the maths wrong, the drug would not work.

Conclusion

The jury is out until we see the results of experiment three, or anecdotal evidence of some home trials. One question I have is how this relates to the  Na_V1.1 ion channels referred to at the beginning of this post.  We know that a defect in this ion channel will produce autism-like symptoms and that these can be reversed (in mice) using the correct type of benzodiazepine, such as clonazepam.  If we find that in a particular child with autism, clonazepam reduces their symptoms and increases cognitive performance, can we claim the route cause was a dysfunction with Na_V1.1 ion channels?  It is a bit of a leap of faith, but I think it is a fair conclusion.  In which case of course, the logical next step would be to look at the underlying gene, SCN1A; that I will leave to people much cleverer than me.

The next question is whether this therapy, which is reducing excitability of the neurotransmitter GABA, is alternative or complementary to bumetanide which is, in effect, doing exactly the same thing.  For that we would need Dr Catterall to talk to Dr Ben-Ari.  

In case you are wondering if there is another connection between Dr Catterall (Clonazepam) and Dr Ben-Ari (Bumetanide), there is.  The same man is part-funding both of these research efforts – Jim Simons, via his Simons Foundation.  As a former hedge fund manager, his is very cleverly hedging his bets. 

 

Clonazepam dosage and effectiveness in Autism