This is a very
brief post to direct those of you interested in the role of GABA, the
neurotransmitter, towards a very recent open access review paper by Ben Ari.
In
particular, people considering Oxytocin or Bumetanide to treat autism may find
it interesting.
My understanding from reading this is the GABA/chloride checkpoint is just one checkpoint of many that could go wrong
ReplyDelete"The GABA/chloride checkpoint is yet another important event of a long chain of informative alterations that signal the developmental stage of a neuron and whether it has successfully implemented its maturation program. This is by no means restricted to GABA and chloride, parallel developmental sequences have been reported in a wide range of systems with similar alterations of ionic currents.”
He then goes on to write:
“I have suggested that neurons that fail to perform their assigned targets and are either misplaced or misconnected remain “frozen” in an immature state that corresponds to the stage at which the developmental sequences was interrupted/modified. In this neuro-archeology concept ( Ben-Ari, 2008), alterations of developmental sequences lead to a persistent electrical or architectural signature of the timing of the failure. In this perspective, developmental disorders are due – at least in part – to the persistent expression of immature currents and oscillations in the adult brain that perturb the operation of well-developed functional networks. This concept has been confirmed in many migration disorders including Double cortex, heterotopic nodules, SRPX2 mutations, where misplaced neurons keep immature features thereby perturbing normo-functioning oscillations ( Ackman et al., 2009, Salmi et al., 2013 and Falace et al., 2014). This concept suggests that the use of specific antagonists /blockers of immature currents in an adult brain might be a useful strategy to block the perturbing activity without altering adjacent networks that have performed adequately their programs. In this model, the persistence of immature currents and aberrant activities and networks is the ultimate cause of disorder. Gene therapy – replacing the mutation by the correct gene – is unlikely to cure as it will not correct the aberrant activities generated by misplaced and misconnected neurons and produce in the crowded adult brain migration and reconnection with the correct targets. Thus, introduction of the Double Cortin gene in neurons that failed to migrate following the invalidation of that gene, partly improved the defaulted migration during the first few days post natal but not later ( Manent et al., 2009). Therefore, to understand and treat brain disorders, it is essential to determine how brain patterns are deviated by the mutation and environmental insult. This coupled with early diagnosis and the use of selective drugs that block the perturbing activities might provide novel therapeutic avenues.”
Have they discovered other checkpoints that we can currently target with ‘specific antagonists /blockers’ (like bumetanide)? I’m wondering for the people where bumetanide doesn’t work or where it works to a point but there are still deficits. Is that because one of these other checkpoints failed further upstream, say one that pertains to calcium or another channel?
I wonder how all this ties into the post you did about parasites. If we evolved having parasites down regulating our immune system through the potassium channel does this alter checkpoints in the brain development of a fetus and if so perhaps that is just the tip of the iceberg in understanding the various ways the hygiene hypothesis is playing out. In essence could parasites or the lack of be changing our brain development including ‘neurotypicals'?
All interesting points.
DeleteThere undoubtedly are other such “checkpoints” that affect autism, many not yet discovered/identified; it might be better to call them “chokepoints”.
One likely one is the function of the receptor MGluR5, where positive allosteric modulators or negative allosteric modulators appear to be able to improve functioning. Some dysfunctions will need positive and some negative modulators as therapy.
Here is one example.
Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning.
http://www.ncbi.nlm.nih.gov/pubmed/23869026
The problem with MGluR5 is that there are no available drugs.
In respect of Ben Ari and his NKCC1 transporter switching GABA from excitatory to inhibitory, I do not think even he has the complete picture.
There is much talk about this excitatory/inhibitory (E/I) balance in both his and other literature. It all assumes that there is a single dimension involved, like the “x” axis in geometry; sometimes it is thought of even more simply as an on/off switch.
I suspect this a gross over simplification, I suspect there are more dimensions or axes to tune, Y and Z etc. Just as you might adjust and gun sight, you need to adjust both horizontal and vertical.
The reason I am saying this is that there is second viable method to “tune” the E/I balance of GABA, this time using the sodium channel Nav1.1. This is possible using micro doses of Clonazepam.
Given that I have already used Bumetanide to “switch GABA from excitatory to inhibitory”, how could Clonazepam have any further effect. But it does.
My conclusion is that there is more to this than just a single axis of excitatory to inhibitory. Or an on/off switch.
I think the Hygiene Hypothesis is interesting, but I believe it is more illustrative than a complete explanation.
I’ve been trying to find the answer for two questions: can you safely give bumetanide to a child with ASD already on valproate treatment and why kids treated with antiepileptic drugs were excluded from Lemonnier trial? Unfortunately I still don’t know that, but I’ve encountered some papers about the other drug, acetazolamide, suggesting that it is able to restore the inhibitory properties of GABA by “inhibition of carbonic anhydrase activity to reduce HCO3-dependent depolarization via GABAA receptors when KCC2 function is compromised” (PMID: 24412803). Acetazolamide was used in other disorders than autism and mostly in mice. Do you think these findings might be of any relevance to ASD?
ReplyDeleteI would suggest you send a short email to Lemonnier and Ben Ari. They do respond when asked interesting questions. In particular, Lemmonier should know all about Valproate and Bumetanide, he must have already thought of combining them.
DeleteI think they want to keep their trials simple and not be subject to any possible drug interactions. I do not think it has to be a safety issue.
I think any drug affecting GABA A or B receptors may have an effect on specific types of autism. Maybe in some types of autism KCC2 function is compromised. It is all interesting.
It looks like you are right.
DeleteChloride homeostasis is controlled by the Na-K-2Cl cotransporter NKCC1 and by the K-Cl cotransporter KCC2 that enhance and lower [Cl−]i, respectively
KCC2 is regulated by neuroligin-2 (NL2)
NLGN2 (neuroligin 2) is a protein-coding gene. Diseases associated with NLGN2 include autistic disorder, and schizophrenia.
I like the laymans language explanation for the mechanism from here - http://www.autismspeaks.org/science/science-news/potent-diuretic-autism-treatment
ReplyDeleteIt is a good explanation.
DeleteVery interesting... but my lack of knowledge makes it hard to understand somethings..
ReplyDeletein your opinion, what would happen if a mother injest GABA supplement during pregnancy?
Aline, it is probably best not to take any drug during pregnancy unless you really need to. In theory GABA does not cross the blood brain barrier, but that is in adults.
DeleteIf you want to reduce the incidence of autism in a yet to be born child, avoid stress during pregnancy and have pets in your house. This protects against eczema, asthma and very likely some autism. The pet "dust" changes the bacteria in your body in a favorable way that adjusts the immune system.
Amazing.. couldn't avoid the stress, but I do have a dog at home :)
DeleteBaby was born in March. I made some use of Gaba suplement , under the thonge in the beginning off the pregnancy. I didn't know by then and also.. didn't though it could cause any harm.
The problem is that baby is showing some problems (since his birth) and I am the one trying to figure out why.
by theory, do you think it can cause harm? I am reading a lot of papers but I am no scientific person... can't understand most of it.
The GABA probably did nothing at all. You cannot usually figure out why some people develop these problems, they are generally caused by multiple factors.
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