Excitotoxicity triggered by GABAa dysfunction

  

This blog, as you will have noticed, does rather meander through science of autism.  As a result there are some gaps and unanswered questions.

The blog talks a lot about the neurotransmitter GABA and the excitatory/inhibitory imbalance.  We have ended up with some therapies based on this that do seem to help many people.

The opposing (excitatory) neurotransmitter is glutamate which affects the NMDA, AMP and mGlu receptors.

It appears that in autism there is an unusually high level of glutamate, but another issue looks likely to be at specific receptors, for example mGluR5

Two routes to autism phenotypes via mGluR5

This does get very complicated and lacks any immediate therapies. 

One very interesting insight was that you can repurpose the existing cheap generic GABA_B drug Baclofen to treat NMDAR-hypofunction. 

This seems to work really well at low doses with many people with Asperger’s.  People with more severe autism do not seem to respond to low doses, however some do to higher doses.  The more potent version R Baclofen is a research drug.

GABAb-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders.

Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA_B-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits.

Excitotoxicity

We have touched on this subject on a few occasions but today, excitotoxicity is the focus of this post.

  

Excitotoxicity looks likely to be present in much autism and helps to connect all the various dysfunctions that we can read about in the literature.

It is a little scary because you cannot know to what extent this process is reversible.  It looks like in milder cases it should be treatable, whereas in extreme cases damage will be irreversible.

Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by neurotransmitters, particularly glutamate. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by glutamatergic storm. 

Unfortunately you can trigger glutamate excitotoxity via a dysfunction in GABA_A receptors.

For example if you severely inhibit GABA_A receptors you kill brain cells, but it was the reaction in glutamate signaling that did the damage.  GABA is supposed to be inhibitory; in some autism it is not and then Glutamate gets out of balance.  This does lead to excess firing of neurons, which seems to degrade cognition, but it will tend towards glutamate excitotoxity.

When you see the cascade of events triggered by glutamate excitotoxity you will see how this really helps to explain biological finding in autism, even mitochondrial dysfunctions.

You can then trace this all back to the faulty GABA switch caused by too little KCC2 and too much NKCC1.

Then you can look at other neurological conditions that feature glutamate excitotoxity, like traumatic brain injury and neuropathic pain, and you see that the research shows low expression of KCC2.

This then suggests that much of autism would have been prevented if you could increase KCC2.  You would not just fix the E/I imbalance but you would avoid all the damage done by excitotoxity.

Just how early you would have to correct KCC2 expression is not clear.  For sure it is a case of better late than never, but how much damage caused by excitotoxicity is reversible?

Good News

The good news is that because KCC2 underexpression is a feature of many conditions there is plenty of research money being spent looking for answers.  When they find a solution for increasing KCC2 to treat neuropathic pain, or spinal cord injury (SCI), the drug can be simply re-purposed for autism.

The French government is funding research into increasing KCC2 to treat SCI.  They are starting with serotin  5-HT_2A receptor agonists.  Regular readers without any memory loss may recall that back in the 1960 Lovaas was giving LSD to people with autism at UCLA.  LSD is a potent 5-HT_2A receptor agonist.  The French are also looking at BDNF to upregulate KCC2 and then they plan to have a blind test where they try all the chemicals they have in their library.  The French are of course doing their trials in test tubes.

When I looked at this subject a while back, I looked for existing therapies that are known to be safe and should be effective.

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?

My conclusion then was that intranasal insulin was the best choice.

Excitoxicity in Autism

Excitotoxicity in the Pathogenesis ofAutism

Autism is a debilitating neurodevelopment disorder characterized by stereotyped interests and behaviours, and abnormalities in verbal and non-verbal communication. It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review

The influx of intracellular calcium triggers the induction of inducible nitric oxide (iNOS) and phosphorylation of protein kinase C. Increased iNOS enhances nitric oxide (NO•) production in excess, whereas protein kinase C activates phospholipase A2 which in turn results in the generation of pro-inflammatory molecules The subsequent generation of free radicals can inhibit oxidative phosphorylation and damage mitochondrial enzymes involved in the electron transport chain, which mitigate energy production .

Reactive intermediates such as peroxynitrates and other peroxidation products hamper the normal function of mitochondrial enzymes by impairing oxidative phosphorylation and inhibiting complex II of the electron transport chain. Moreover, lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) can interact with synaptic protein and impair transport of glucose and glutamate, thereby decreasing energy production and increasing excitotoxic sensitivity

Overstimulation of the glutamate receptors, NMDA and AMPA, leads to the release of other excitotoxins resulting in the accumulation of glutamate. Indeed, excess glutamate concentrations results in an increase in calcium levels in the cytosol. This effect is attributed to the fact that excessive glutamate allows calcium channel to open for longer periods of time, leading to increased influx of calcium into cells. Calcium triggers inducible nitric oxide and protein kinase C that produce free radicals, ROS and arachidonic aid. Generation of these oxidants results in mitochondrial dysfunction and accumulation of pro-inflammatory molecules and finally cell death. Free radicals interact with the mitochondrial and cellular membrane to form lipid peroxidation. 4-HNE is a major destructive product of this process. Lipid peroxidation prevents the dephosphorylation of excessively phosphorylated tau protein, significantly interfering with microtubule function. It has also been shown to inhibit glutathione reductase needed to convert oxidised glutathione to its functional reduced form

The mechanism responsible for excitotoxicity and neuronal cell death is diverse. Experimental studies have shown that the apoptotic and/or necrotic cell death may be due to the severity of NMDA damage or can be dependent on receptor subunit composition of neurons (Bonfoco et al. 1995; Portera-Cailliau et al. 1997). Pathological events related to this mode of action can be loss of cellular homoeostasis with acute mitochondrial dysfunction leading to hindrance in ATP production. Moreover, glutamatergic insults can cause cell death by the action of one or more molecular pathways which involves the action of signaling molecules such as cysteine proteases, mitochondrial endonucleases, peroxynitrite, PARP-1 and GAPDH in the excitotoxic neurodegeneration pathway.

Intracellular calcium levels also rely on voltage-dependent calcium channels and Na exchangers . The Na?/Ca2? exchanger is a bi-directional membrane ion transporter, which during membrane depolarisation or the opening of the gated sodium channels, transports sodium out of the cell and calcium into the cell. AMPA-type glutamate receptors are highly permeable to calcium and its over expression can lead to excitotoxicity. The Ca2? permeability capability of AMPA-type glutamate receptors relies on the presence or the absence of the GluR2 subunit in the receptor complex. Reduced GluR2 expression permits the construction of AMPA receptors with high Ca2? permeability and contributes to neuronal defect and excitotoxicity. Another mechanism is the release of calcium from internal stores such as the endoplasmic reticulum and mitochondria. It results in mitochondrial dysfunction, reduction in ATP synthesis and ROS generation.

Voltage gated channels found in dendrites and cell bodies of neurons modulate neuronal excitability and calcium-regulated signaling cascades (Dolmetsch et al. 2001; Catterall et al. 2005). Point mutations in the gene encoding the L-type voltage-gated channels Ca v1.2 (CACNA1C) and Ca v1.4. (CACNA1F) prevent voltage-dependent inactivation of these genes. This causes the channel to open for longer time, leading to excessive influx of calcium.

Conclusion

Autism is a multifactorial disorder characterized by neurobehavioral and neurological dysfunction. Excitotoxicity is the major neurobiological mechanism that modulates diverse risk factors associated with autism. It is triggered by potential mutation in ion channels and signalling pathways, viral and bacterial pathogens, toxic metals and free radical generation. Over expression of glutamate receptors and increased glutamate levels leads to increased calcium influx and oxidative stress and progressive cellular degeneration and cell death. Genetic defect, such as mutation in voltage gated or ligand channels that regulate neuronal excitability leads to defect in synaptic transmission and excitotoxic condition in autism. Mutation in BKCa and Ca v1.2 channels also results in excess calcium influx Sodium, potassium and chloride channels also play important roles in maintaining homoeostasis of neuronal cells, and decreased channel activity leads to destabilization of membrane potential and excitotoxicity. Moreover, over expression of BDNF results in hyperexcitability. Excessive BDNF and NMDA receptor activity increases the neurotransmitter release and excitotoxic vulnerability. Given that autism is a multifaceted disorder with multiple risk factors, more precise studies are needed to explore the signalling pathways that influence emergence of excitotoxicity in ASDs.

Some relevant reading for those interested:-

GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders

Abstract

Background

Autism spectrum disorder (ASD) is characterized by three core behavioral domains: social deficits, impaired communication, and repetitive behaviors. Glutamatergic/GABAergic imbalance has been found in various preclinical models of ASD. Additionally, autoimmunity immune dysfunction, and neuroinflammation are also considered as etiological mechanisms of this disorder. This study aimed to elucidate the relationship between glutamatergic/ GABAergic imbalance and neuroinflammation as two recently-discovered autism-related etiological mechanisms.

Methods

Twenty autistic patients aged 3 to 15 years and 19 age- and gender-matched healthy controls were included in this study. The plasma levels of glutamate, GABA and glutamate/GABA ratio as markers of excitotoxicity together with TNF-α, IL-6, IFN-γ and IFI16 as markers of neuroinflammation were determined in both groups.

Results

Autistic patients exhibited glutamate excitotoxicity based on a much higher glutamate concentration in the autistic patients than in the control subjects. Unexpectedly higher GABA and lower glutamate/GABA levels were recorded in autistic patients compared to control subjects. TNF-α and IL-6 were significantly lower, whereas IFN-γ and IFI16 were remarkably higher in the autistic patients than in the control subjects.

Conclusion

Multiple regression analysis revealed associations between reduced GABA level, neuroinflammation and glutamate excitotoxicity. This study indicates that autism is a developmental synaptic disorder showing imbalance in GABAergic and glutamatergic synapses as a consequence of neuroinflammation.

Keywords: Autism, Glutamate excitotoxicity, Gamma aminobutyric acid (GABA), Glutamate/GABA, Tumor necrosis factor-α, Interleukin-6, Interferon-gamma, Interferon-gamma-inducible protein 16

Postmortem brain abnormalities of the glutamate neurotransmitter system in autism.

CONCLUSIONS:

Subjects with autism may have specific abnormalities in the AMPA-type glutamate receptors and glutamate transporters in the cerebellum. These abnormalities may be directly involved in the pathogenesis of the disorder.

Pathophysiologyof traumatic brain injury

General pathophysiology of traumatic brain injury

The first stages of cerebral injury after TBI are characterized by direct tissue damage and impaired regulation of CBF and metabolism. This ‘ischaemia-like’ pattern leads to accumulation of lactic acid due to anaerobic glycolysis, increased membrane permeability, and consecutive oedema formation. Since the anaerobic metabolism is inadequate to maintain cellular energy states, the ATP-stores deplete and failure of energy-dependent membrane ion pumps occurs. The second stage of the pathophysiological cascade is characterized by terminal membrane depolarization along with excessive release of excitatory neurotransmitters (i.e. glutamate, aspartate), activation of N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate, and voltage-dependent Ca²⁺- and Na⁺-channels. The consecutive Ca²⁺- and Na⁺-influx leads to self-digesting (catabolic) intracellular processes. Ca²⁺ activates lipid peroxidases, proteases, and phospholipases which in turn increase the intracellular concentration of free fatty acids and free radicals. Additionally, activation of caspases (ICE-like proteins), translocases, and endonucleases initiates progressive structural changes of biological membranes and the nucleosomal DNA (DNA fragmentation and inhibition of DNA repair). Together, these events lead to membrane degradation of vascular and cellular structures and ultimately necrotic or programmed cell death (apoptosis).

Excitotoxicity and oxidative stress

TBI is primarily and secondarily associated with a massive release of excitatory amino acid neurotransmitters, particularly glutamate.⁸⁵⁴ This excess in extracellular glutamate availability affects neurons and astrocytes and results in over-stimulation of ionotropic and metabotropic glutamate receptors with consecutive Ca²⁺, Na⁺, and K⁺-fluxes.²²⁷³ Although these events trigger catabolic processes including blood–brain barrier breakdown, the cellular attempt to compensate for ionic gradients increases Na⁺/K⁺-ATPase activity and in turn metabolic demand, creating a vicious circle of flow–metabolism uncoupling to the cell.¹⁶⁵⁰

Oxidative stress relates to the generation of reactive oxygen species (oxygen free radicals and associated entities including superoxides, hydrogen peroxide, nitric oxide, and peroxinitrite) in response to TBI. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system (e.g. superoxide dismutase, glutathione peroxidase, and catalase) induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain.³¹¹⁶⁰ Although these mechanisms are adequate to contribute to immediate cell death, inflammatory processes and early or late apoptotic programmes are induced by oxidative stress.¹¹

Knocking down of the KCC2 in rat hippocampal neurons increases intracellular chloride concentration and compromises neuronal survival

Non-technical summary

‘To be, or not to be’– thousands of neurons are facing this Shakespearean question in the brains of patients suffering from epilepsy or the consequences of a brain traumatism or stroke. The destiny of neurons in damaged brain depends on tiny equilibrium between pro-survival and pro-death signalling. Numerous studies have shown that the activity of the neuronal potassium chloride co-transporter KCC2 strongly decreases during a pathology. However, it remained unclear whether the change of the KCC2 function protects neurons or contributes to neuronal death. Here, using cultures of hippocampal neurons, we show that experimental silencing of endogenous KCC2 using an RNA interference approach or a dominant negative mutant reduces neuronal resistance to toxic insults. In contrast, the artificial gain of KCC2 function in the same neurons protects them from death. This finding highlights KCC2 as a molecule that plays a critical role in the destiny of neurons under toxic conditions and opens new avenues for the development of neuroprotective therapy.

New understanding of brainchemistry could prevent brain damage after injury

Sciences de la vie, de la santé et des écosystèmes : Neurosciences (Blanc SVSE 4) 2010
Projet KCC2-SCI

The potassium-chloride transporter KCC2 : a new target for the treatment of neurological diseases

A decrease in synaptic inhibition –disinhibition- appears to be an important substrate in several neuronal disorders, such as spinal cord injury (SCI), neuropathic pain... Glycine and GABA are the major inhibitory transmitters in the spinal cord. An important emerging mechanism by which the strength of inhibitory synaptic transmission can be controlled is via modification of the intracellular concentration of chloride ions ([Cl-]i) to which receptors to GABA/glycine are permeable. Briefly, a low [Cl-]i is a pre-requisite for inhibition to occur and is maintained in healthy neurons by cation-chloride co-transporters (KCC2) in the plasma membrane, which extrude Cl-. We showed recently (Nature Medicine, accepted for publication) that these transporters are down-regulated after SCI, thereby switching the action of GABA and glycine from inhibition to excitation; this can account for both SCI-induced spasticity and chronic pain. KCC2 transporters therefore appear as a new target to restore inhibition within neuronal networks in pathological conditions. The present project aims at reducing spasticity and chronic pain after SCI by up-regulating KCC2. 
An important part will consist in identifying new compounds that increase the cell surface expression and/or the functionality of KCC2. Two strategies are considered. 1) Serotonin and BDNF will be tested on the basis of preliminary experiments and/or previous reports in other areas of the central nervous system indicating that these two compounds may affect the expression of KCC2. 2)Testing a large amount of compounds available in a library (“blind test”) to sort out KCC2-modulating molecules. This task can only be done in vitro on an assay that enables to easily visualize and quantify cell surface expression of KCC2, in response to these molecules (HEK293 cells). The few compounds isolated at the end of this task will then be tested on cultures of motoneurons (both mouse motoneurons and human motoneurons derived from induced pluripotent cells) and characterized further (potential toxicity, ability to cross the Brain Blood Barrier and effect on internalization and endocytosis of KCC2). 
The selected candidate compounds will enter into the in vivo validation phase aimed at increasing the expression of KCC2 following spinal cord injury (SCI; both contusion and complete spinal cord transection). The selected hits will be applied by intrathecal injections in SCI rats and their effects on KCC2 expression in the plasma membrane of motoneurons will be tested by means of western blots and immunohistochemistry. Their efficacy in increasing the cell-surface expression of KCC2 will also be tested electrophysiologically in vitro (i.e. their ability to hyperpolarize ECl). Functionally, their efficacy in reducing both SCI-induced spasticity and chronic pain will be assessed. 
Genetic tools will be used to increase the expression of KCC2 in some spinal neurons. This task will be done in collaboration with teams in the USA. Lentiviral vectors aimed at increasing KCC2 in the host cells, after parenchymal injection, have been developed in San Diego. A transgenic mouse model with a conditional tamoxifen-induced overexpression of KCC2 has been developed in Pittsburgh. The rationale for this part of the project is to use these genetic tools in the chronic phase of SCI to reduce spasticity and chronic pain. 
The last part of the project will focus on more fundamental issues regarding the relationship between the SCI-induced downregulation of KCC2 and the development of spasticity and chronic pain. 
The significance of the expected results goes far beyond the scope of SCI, since altered chloride homeostasis resulting from mutation or dysfunction of cation-chloride cotransporters has been implicated in various neurological disorders such as, for instance, ischemic seizures neonatal seizures and temporal lobe epilepsy. 

KCC2 escape from neuropathic pain

Activationof 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2.

 In healthy adults, activation of γ-aminobutyric acid (GABA)(A) and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl(-)](i)), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E(IPSP), in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT(2A) receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT(2A)R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).

Conclusion

Very little is certain in autism, in great part because only about 200 brains have ever been examined post mortem.  There are many theories, but very many more sub-types of autism.

GABA_A dysfunction due to the faulty GABA switch never increasing KCC2 expression in the first weeks of life, triggering glutamate excitotoxicity and all that follows would go a long way to explaining my son’s type of autism. It might well explain 30+% of all autism.

Clearly other causes of excess glutamate would lead to a similar result.

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.

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.