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Showing posts with label Homeostasis. Show all posts
Showing posts with label Homeostasis. Show all posts

Wednesday 24 June 2015

Altered Homeostasis in Autism: Cl-, K+, Ca2+, and quite possibly Zn2+



Today’s post will highlight how, perhaps, in 50 years’ time, autism might be understood by the non-scientist.  Sometimes it helps to oversimplify a complex problem in order not to get lost in all the complexities and see what underlying mechanisms may exist.


Homeostasis

Homeostasis is a fancy word for balance or equilibriumIt is the property of a system in which variables are regulated so that internal conditions remain stable and relatively constant.

All living organisms depend on maintaining a complex set of interacting metabolic chemical reactions. From the simplest unicellular organisms to the most complex plants and animals, internal processes operate to keep the conditions within tight limits to allow these reactions to proceed. Homeostatic processes act at the level of the cell, the tissue, and the organ, as well as for the organism as a whole.

Many diseases involve a disturbance of homeostasis.

Autism is clearly a condition of altered homeostasis, but not severe enough as to become degenerative.


First Chloride Cl-, Calcium Ca2+ , then Potassium K+ and now perhaps Zinc Zn2+

We have already seen that three very simple ions, chloride Cl- , calcium Ca2+, potassium K+ are in the “wrong place” or in the “wrong concentration” in autism.  This in effect tells us that there is altered homeostasis.

Would it then come as a surprise that a fourth ion, zinc Zn2+ also appears to be in the “wrong place”, in at least some autism?

Perhaps there is a common mechanism behind this dysfunctional homeostasis? It might be related to cell adhesion molecules like neuroligins (see below), which will be looked at in another post.



Source: By Sarahlobescheese (Created on Paintbrush and Microsoft Word) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons


Supplementation and Homeostasis

When the lay person hears that something simple is involved in the pathology of autism, the immediate reaction seems to be that you either need more, or less, of it.  So more calcium, more zinc, more magnesium etc.

The problem is more complex; there is enough calcium (and your bones are full of it) but it is not all quite in the right place, so it needs moving around a bit.

When I came across the recent research from Taiwan about the effect of zinc on the NMDA receptors in the brain, I did a quick check and found lots of people supplementing zinc. Some people because the level in their child’s hair was high and some because it was low; the therapy remained the same, more zinc.

Just as Ben-Ari really has figured out many aspects of the excitatory/inhibitory imbalance in GABA in autism and chosen a therapy that indirectly corrects it, the Taiwanese have also gone into their receptor, the NMDA, in detail.  They put forward a well thought out case for modulating it.

Just as Ben Ari choose to move chloride to outside the cells with his drug (Bumetanide), Yi-Ping Hsueh, the Taiwanese researcher, uses an existing  drug called Clioquinol to move zinc from a presynaptic terminal to postsynaptic sites in the brain.  Again, like Ben Ari, she also showed it to be effective in two different mouse models of autism.



“Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation



Scientists compared the interactions of test mice by placing the subjects in a box, mice that had been unchanged, mice with their Tbr1 and Shank2 proteins “knocked off” and another “stranger” mouse.
They found that unchanged mice engaged in high-level interaction with the “stranger” mouse, while mice with Tbr1 and Shank2 deficiencies interacted very little.
Hsueh’s team had previously determined that Tbr1 is a contributing factor of autism, while a team led by South Korean scientist and project coleader Eunjoon Kim discovered that Shank2 is also implicated in the condition.
Both deficiencies hamper the transmission of zinc ions to the NMDAR (N-methyl-D-aspartate) receptor, impairing function.
About 30 percent of children with autism suffer from zinc deficiency.
Hsueh said that previous projects had determined that autism is linked to zinc deficiency, but the research undertaken by Academia Sinica and the South Korean researchers is the first to provide a scientific explanation for the phenomenon by establishing that the social inhibitions caused by autism can be changed by revitalizing the NMDAR receptor.
Hsueh said the results from the experiment conducted on mice can be extrapolated to humans, with a higher than 90 percent relevance between the two species.
She said that as clioquinol is a prescription drug permitted in Taiwan, her team hopes psychiatrists will prescribe the drug to suitable patients.



Zinc Deficiency or Zinc Transmission Deficiency?

A quick review of the research does show very odd levels of zinc in people with autism.  It also transpires that different ways of measuring zinc levels (hair, blood etc) can produce the opposite result.  So it is hard to ascertain that somebody really does have a zinc deficiency.

The key point is the transmission of that Zinc to the NMDA receptors in the brain.  Note the Zn2+ modulatory site in the diagram below.





Clioquinol

Clioquinol, has a very tainted past in Japan. The drug was widely used for various conditions in the 1960s, at doses higher than in other countries.  Its use was tied to the emergence of a new condition called Subacute myelo-optico-neuropathy (SMON) , which only seems to have occurred in Japan.

Clioquinol is banned in some countries, but widely available in other countries, like Taiwan,

Clioquinol is showing promise in research into Alzheimer’s.

Some argue that Clioquinol is totally safe and argue for a combined therapy of Clioquinol and zinc.





Conclusions

These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.

  


Subacute myelo-optico-neuropathy (SMON) is a disease characterized by subacute onset of sensory and motor disorders in the lower half of the body and visual impairment preceded by abdominal symptoms. A large number of SMON were observed throughout Japan, and the total number of cases reached nearly 10,000 by 1970. Despite clinical features mimicking infection or multiple sclerosis, SMON was confirmed as being caused by ingestion of clioquinol, an intestinal antibacterial drug, based on extensive epidemiological studies. After the governmental ban on the use of clioquinol in September 1970, there was a dramatic disappearance of new case of SMON. In the 1970s, patients with SMON initiated legal actions against the Government and pharmaceutical companies, and the court ruled that the settlements would be made as health management allowances and lasting medical check-ups. The physical condition of patients with SMON remains severe owing to SMON as well as gerontological complications. The pathological findings in patients with SMON included symmetrical demyelination in the lateral and posterior funiculi of the spinal cord and severe demyelination of the optic nerve in patients with blindness. Although clioquinol may show activity against Alzheimer's disease or malignancy, its toxic effects cause severe irreversible neurological sequelae. Thus, caution must be exercised in the clinical use of clioquinol



Zinc is an essential micronutrient that accumulates in brain and is required for normal development and function. Both deficiency and excess of zinc alter behavior and can cause brain abnormalities and neuropathies, of which epilepsy, ischemia, and Alzheimer’s degeneration have been the most studied. Aside from catalytic and structural functions in many proteins, ionic zinc (Zn2+) may play important roles in neurotransmission. Free Zn2+ accumulates in the synaptic vesicles of a specific subset of glutamatergic neurons and is coreleased with glutamate in an activity-dependent manner. Upon release, free Zn2+ may modulate neurotransmitter receptors and transporters, activate zinc-sensing metabotropic receptors, and/or gain cellular access through Ca2+-permeable channels. At certain glutamatergic synapses, a primary role for vesicular zinc is to reduce N-methyl-D-aspartate (NMDA) receptor currents . A wide range of extracellular Zn2+ concentrations directly and specifically inhibit NMDA receptor responses, and in the hippocampus, a region highly enriched in vesicular zinc, zinc-positive glutamatergic synapses are also enriched in NMDA receptors. The inhibitory effects of Zn2+ on NMDA receptors have received considerable attention due in part to the pivotal role played by these receptors in synaptic transmission and plasticity. Still, the mechanism by which the inhibition occurs is incompletely understood.


Other ways of modifying NDMA receptors

As the excellent recent paper below from Korea points out,correcting NMDAR dysfunction has therapeutic potential for ASDs”.  The problem is that in some autism there is too much NMDAR function, and in others there is too little.

So we should not expect much success from any “one size fits all” therapy.


NMDA receptor dysfunction in autism spectrum disorders.


Abnormalities and imbalances in neuronal excitatory and inhibitory synapses have been implicated in diverse neuropsychiatric disorders including autism spectrum disorders (ASDs). Increasing evidence indicates that dysfunction of NMDA receptors (NMDARs) at excitatory synapses is associated with ASDs. In support of this, human ASD-associated genetic variations are found in genes encoding NMDAR subunits. Pharmacological enhancement or suppression of NMDAR function ameliorates ASD symptoms in humans. Animal models of ASD display bidirectional NMDAR dysfunction, and correcting this deficit rescues ASD-like behaviors. These findings suggest that deviation of NMDAR function in either direction contributes to the development of ASDs, and that correcting NMDAR dysfunction has therapeutic potential for ASDs.

Pharmacological modulation of NMDAR function can improve ASD symptoms. D-cycloserine (DCS), an NMDAR agonist, significantly ameliorates social withdrawal  and repetitive behavior  in individuals with ASD.

These results suggest that reduced NMDAR function may contribute to the development of ASDs in humans. Elevated NMDAR function is also implicated in ASDs. Memantine, an NMDAR antagonist, and its analogue amantadine improve ASD-related symptoms including social deficits, inappropriate language, stereotypy, cognitive impairments, lethargy, irritability, inattention, and these results, together with the DCS results, highlight the importance of a normal range of NMDAR function, and suggest that deviation of NMDAR function in either direction leads to ASD.  This concept is in line with the emerging view that synaptic function within a normal range is important and its deviation causes ASDs and intellectual disability

Mice lacking neuroligin-1, an excitatory postsynaptic adhesion molecule, show reduced NMDAR function in the hippocampus and striatum, as evidenced by a decrease in NMDA/AMPA ratio and long-term potentiation (LTP) Neuroligin-1 is thought to enhance synaptic NMDAR function, by
directly interacting with and promoting synaptic localization of NMDARs.

CDPPB, a positive allosteric modulator of mGluR5 that potentiates similarly normalizes NMDAR Dysfunction and behavioral deficits, consistent with the idea that indirectly modulating NMDARs through mGluR5 is a viable approach for treating ASDs.

ASDs involve diverse core and comorbid symptoms. Consistent with this, a single autism-related mutation, neuroligin-3 R451C, causes diverse synaptic phenotypes in different brain regions and circuits. Therefore, synaptic changes should be analyzed in greater detail, ideally using brain region-specific and cell type-specific conditional gene ablation, as recently reported.

Modulators of mGluR5, in addition to NMDARs and AMPARs, have been considered to be a new means of regulating glutamatergic transmission. Therefore, pharmacological rescue of animal models of ASD should ideally involve modulation of both NMDARs and mGluR5, or even other NMDA-modulatory approaches, to better facilitate translation to clinical therapy.

Lastly, because our hypothesis associates bidirectional NMDAR dysfunction with ASDs, there may be clinical cases, such as where individuals with reduced NMDAR function are treated with NMDAR antagonists, which might aggravate the situation and affect the interpretation.



None of the existing autism therapies that modify NDMA receptors have been uniform knockout successes, but are effective in some cases.



These include:-

·        Memantine an NMDAR antagonist
·        D-Cycloserine an NMDAR agonist (the opposite of Memantine)

·        Ketamine, an NMDAR antagonist



So if you respond to Memantine, the chances are you would benefit from intranasal ketamine;  but D-Cycloserine would make you worse.

They recently terminated early the large Memantine autism trial.  In a rational world they would try D-Cycloserine on all those kids who failed to respond to Memantine.  We do not live in a rational world.



Conclusion

I have a feeling that several dysfunctions in autism, including the E/I imbalance of GABA, will ultimately be traced back to neuroligins.

This is an area of science in its infancy and so for today we have to treat the consequences individually. 

Fortunately, the Simons Foundation is funding the right people and so, in the end, we will get to the bottom of it all.




I hope the Taiwanese test Clioquinol on some humans with ASD and let us know the results.  

As the clever Korean researcher above has highlighted, Clioquinol will only benefit those with reduced NMDAR function.  So if I have got things the right way round, Clioquinol will help the same group that respond to D-Cycloserine.  The others would need Memantine/Ketamine, or even better, they have perfect NMDAR function and need nothing at all.








Sunday 7 April 2013

Conceptual Map of Behavioural Homeostasis in Autism

In the research there are various scales to measure how autistic a child is, for example the Childhood Autism Rating Scale (CARS).  They are very subjective, but clearly better than nothing at all. I read a study on older children with ASD that was highlighting that as the children get older, they become less autistic.  In the CARS scale there are 14 behavioural areas to grade and then there is number 15, which is the general impression of the clinician.  In effect, number 15 is how autistic the clinicians feel the subject to be;  you would expect that number 15 would be consistant with the findings in the first 14 areas.  In the test the older children all showed a big improvement in areas 1 to 14, but not in number 15, which is the one that really matters.  This really means that either the use of CARS was inappropriate or CARS is flawed.

As children get older the concept of "normal" changes.  So there is not much point comparing a 15 year old with ASD to a normal/typical 3 year old.  So I decided that kids with ASD deserve a better framework, so that clinicians and parents have a better way to understand many important issues, ranging from prognosis, to just what is autism and where its boundaries really are.

In the Peter Autism Scale (PAS), typical kids start at birth with a score of zero. After 12 months, typical kids show rapid development; they acquire an increasingly negative PAS score. After puberty has ended, the PAS score stops declining and gradually heads back towards minus 20.  Much later in life, after starting their own family, the PAS drifts back up towards minus 10.


Autistic children are likely born with a positive PAS score; as they show either regression, or just the emergence of ASD-type behaviours, the score will increase. At a score of 60, self injurious behaviour is exhibited; at a score of 80 there is serious aggression and violence. The scale stops at 100, where the child needs physical restraint and is likely to be sent to an institution (depending on which country they live in).


There has been an explosion in the number of children diagnosed with ASD, most notably in the US.  Undoubtedly a great deal of this is explained by a bizarre, ever-widening of the definition of autism.  At one end of the scale, what were formerly nerds/geeks are now "on the spectrum" and at the other end of the scale, cases of mental retardation (MR) are now labeled as severe autism.  This ever changing, ever stretching, diagnosis is extremely harmful to the search for genuine therapies.

Mild social difficulties and obsession with computers or music is nothing new; it may indeed be worthy of a diagnostic term, but I do not think it is autism, or ASD.  On the PAS framework, you will note a blue cloud.

Asperger's syndrome already has a nice name; in the PAS conceptual map it follows in parallel the general path of typical development but has a score 12 higher.  It passes through the lower edge of the blue cloud.



Now to the serious case of what I shall term "disabling autism".  These are children with a PAS score of greater than 20.  These children need immediate therapy and their parents need external training and support.  If this help is received, there is good chance that the PAS score will never reach 60, let alone 80.  If help is not received and the PAS reaches 100, there will not be a happy ending.

In a perfect world, the prompt intervention (both behavioural and pharmacological) will give the child a fighting chance of gradually heading south to that big blue cloud.



Monty no BU no NAC
This is my estimation of Monty's development with no drugs
 
Monty + NAC
This is my estimated outcome using NAC alone
 
Monty + BU + NAC
This is my curreent prognosis using Bumetanide and NAC
 
Monty + BU + NAC + Agent X
This is my optimal prognosis achieved by adding the unkown Agent X


Monty himself is the first subject to have a PAS assessment.  Clearly this is just conceptual and so is purely illustrative;  nonetheless I think it has value.

Monty was not born a typical baby; he was always a bit different.  These differences grew and it was in his fourth year that he really began to acquire and demonstrate lots of new skills.  Then, with a great deal of behavioral support, it was plain sailing until he was about 8 and a half years old, when almost overnight, his world fell apart.  His longtime assistant had to leave him and his cosy world was overturned.  All the behaviours that he had avoided earlier, such as head banging and aggression to others, emerged with a vengeance.  Nine months later things had finally returned to "normal", but at a higher plateau of autism than 12 months before.

Three months later I trialed Bumetanide (BU in the chart) and three months after that plateau I trialed NAC.  In the PAS framework, Bumetanide appeared to provide a one-off 40% reduction.  Then with NAC, I took a wild guess at a 25% one-off reduction in PAS score.

Now we are in sight of the blue cloud, but a lot of work remains to be done.

Within 12 months, I would like to have found Agent X, which would give another 25% reduction in PAS score.  I think that will be as much help as can be reasonably expected from drugs.     

If it was not for puberty, it would be plain sailing into the future.  In the prediction, I have forecast another behavioral meltdown (loss of behavioural homeostatis), but since we now have experience of such a shock, I hope to manage it better.