UA-45667900-1
Showing posts with label neuroligins. Show all posts
Showing posts with label neuroligins. Show all posts

Wednesday 3 February 2021

Vasopressin, Oxytocin, the Lateral Septum, Aggression and Social Bonding, Autism gene NLGN3 and MNK inhibitors for reversing Fragile-X and likely more Autism

 

The Lateral Septum, in green, turns the volume

 up or down in aggression


Today’s post started by me checking for anything new in the research about the hormone Vasopressin and autism. I was surprised by just how much research continues to be published on the subject – no smoke without fire, perhaps.

We also get another insight into how aggressive raging develops in the brain; we even have a photo.

A novel therapy for Fragile-X is also thrown into the mix, due to a link to oxytocin.

So, what is cooking in the research?

The first thing to note is that you really do have to look at both Oxytocin and Vasopressin, because these two hormones are very closely related.

We have previously looked at the autism gene NLGN3, this gene encodes the cute sounding neuroligin-3.

 

https://epiphanyasd.blogspot.com/search/label/neuroglin

 

The reason people with Fragile-X have autism is because they lack the protein FMRP (Fragile X mental retardation protein).

In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

When you look at the interactions of the FMRP protein you can find ways to compensate for this deficiency.  This is nicely illustrated in the graphic below. You just need to find another way to influence elF4E and elF4G.

Some people have told me they find these charts a bit overwhelming, but they precisely show what is going on.  You just have to look up all the terms, you do not know.  In the chart below there is NF1 autism, there is PTEN autism, problems with Ras are called RASopathies and cause MR/ID plus autism. We have at least one reader with TSC (Tuberous sclerosis) type autism. We have readers whose kids lack FMRP, because they have Fragile-X syndrome. 

Today we see that an inhibitor of MnK (in yellow in the chart below) is another via option to treat Fragile-X.

Beyond Fragile-X, we can see that numerous other upstream dysfunctions in the chart can result in miss-expression of neuroligins (NLGNs) in the chart below and then result in autism.

 


 One of the papers below goes further and suggests

“This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses”

“We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis”

“Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome to a non-syndromic model of ASD”

 

Regarding Fragile X 

“Collectively, this work establishes eFT508 (an MNK inhibitor) as a potential means to reverse deficits associated with FXS.”

 

What is the connection to Oxytocin?

A problem with your neuroligins causes an impairment in oxytocin signalling.

 

The role of the Lateral Septum (LS) in both aggression and desirable social behavior 

If you scan through the research on vasopressin and oxytocin you will eventually come across references to the LS.  The LS is a part of your brain called the Lateral Septum.

In the picture below you see a mouse brain and the green part is the Lateral Septum (LS).

 

Source: https://neurosciencenews.com/rage-lateral-septum-3637/ 

“Our research provides what we believe is the first evidence that the lateral septum directly ‘turns the volume up or down’ in aggression in male mice, and it establishes the first ties between this region and the other key brain regions involved in violent behavior”


Both social bonding and offensive aggression involve vasopressin receptors in a part of the brain called the Lateral Septum (LS).  Activity in the Lateral Septum (LS) is regulated by inhibitory GABA, and excitatory glutamate.

There is a notable difference between males and females, at least in rats.  No sex differences were found in extracellular GABA concentrations during social playing; however, glutamate plays a major role in female social playing. When glutamate receptors are blocked in the LS pharmacologically, there is a significant decrease in female social playing, while males had no decrease in playing. This suggests that in the lateral septum, GABA neurotransmission is involved in social play behavior regulation in both sexes, while glutamate neurotransmission is sex-specific, involved in regulation of social play only in females.

 

Aggressive behavior in females 

Neural mechanisms of female aggression: Implications on the oxytocin and vasopressin systems

These models allowed me to investigate the role of the brain oxytocin (OXT) and vasopressin (AVP) systems on aggressive behavior. Both neuropeptides are known to regulate social including aggressive behaviors in males and lactating females.

Taken together this part of my thesis shows that the balance between OXT and AVP release within the LS regulates female aggression in a receptor and region-specific manner via modulating GABAergic neurotransmission.

Overall, this thesis shows that females are able to develop escalated as well as abnormal aggression just like males. In addition, the OXT and the AVP system seem to be main players in regulating aggressive behavior in female Wistar rats, especially, regarding their role in controlling aggression by acting on the LS.

 

The effect of Vasopressin as a therapy

 

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model 

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

 

In humans, intranasal administration of AVP increased activity in the LS and reciprocated social collaboration (47). Intranasal OXT administration enhances the suppression of oscillatory activity (8–25 Hz) during execution and observation of social actions (48). Altogether, OXT- and AVP-dependent modulation of neural activity in response to social stimuli directly affect EEG activity, which may have a predictive value for the impact of such treatment in ASD-associated disorders. Furthermore, an imbalance between inhibition and excitation is associated with ASD, and AVP treatment could reset the balance by altering the functions of SST neurons (49).

  

Predicting Autism measuring Neonatal CSF vasopressin concentration 

We have yet another predictor of future autism.


Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder


The Russian paper below is very thorough. At least in the case of autism, I do not agree with the therapeutic implications.  The paper suggests Oxytocin agonists (like oxytocin itself) and Vasopressin antagonists.

I propose Oxytocin agonists and Vasopressin agonists, as a practical solution today.  It is not a perfect solution, but totally doable today.

  

The role of oxytocin and vasopressin dysfunction in cognitive impairment and mental disorders 

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

 

4.4. Autism

Autism spectrum disorder (ASD) is a group of disorders that are characterized by early disturbances of social communication and limited, repetitive behaviour. Individuals with autism have impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. Additionally, they exhibit atypical neural development at the systems level . Autism is characterized by a disturbance of social interaction first of all, but it is also characterized by cognitive dysfunctions, including working memory impairment. The OXT/AVP system plays a role in such deficits. In male mice with a mutation in the Magel2 gene, social behaviour and cognitive functions are disrupted in adulthood, which makes this model similar to ASD. The lack of Magel2 causes a change in the OXT system. Subcutaneous administration of OXT to mice with this mutation during the first week of life suffices to restore normal social behaviour and learning abilities in adult mice. Exogenous OXT stimulates the release of endogenous OXT and inhibits the accumulation of intermediate forms of OXT (this is observed in OXT neurons in mice with the Magel2 mutation). This was revealed by neuroimaging methods. Human ASD is associated with altered face processing and decreased activity in brain areas involved in this process. OXT enhances the importance of social stimulus in ASD, and probably can stimulate face processing and eye contact in people with ASD. Genetic polymorphisms of the OXT and AVP receptor genes are associated with ASD. Additionally, this review revealed a link between social cognition disorders in autism and some SNPs in the OXTR and V1a receptor genes. The most significant associations between SNPs in OXTR and social cognition were found for rs2254298, rs53576 and rs7632287. SNP rs2254298 has been associated with a diagnosis of ASD. SNP in the V1a receptor gene, rs7294536, is closely associated with a deficit in social interactions. In addition, OXTR rs237887 polymorphism affects facial recognition memory in families with autistic children.

 




 

 

 

Fig 1. The role of oxytocin and vasopressin systems in the pathogenesis of mental disorders. Stress activates the HPA axis and rises in plasma glucocorticoid levels, which leads to social through the cortisol release. HPA axis activation increases the risk of development of psychopathologies. OXT and AVP regulate emotional behaviours, multiple aspects of social behaviour and cognitive functions. Negative environment, including stress factor, causes an imbalance of the OXT/AVP system, which also leads to psychopathological behaviour: aggression, social impairment, anxiety, emotional and cognitive disorders. At the same time, the OXT/AVP system forms a reaction to stress oppositely. OXT inhibits the HPA axis stress induced activity (anxiolytic effect). AVP activates the HPA axis (anxiogenic effect). OXT and AVP can be used as the treatment of mental diseases associated with social and cognitive dysfunctions. OXT – oxytocin; AVP – arginine-vasopressin; iOXT – intranasal oxytocin; iAVP – intranasal arginine-vasopressin; ACTH - adrenocorticotropic hormone; CRH – corticotropin releasing hormone; HPA axis - hypothalamic-pituitary-adrenal axis.

 

 

5. OXT and AVP systems in mental disorder treatments in recent years, interest in the usage of OXT as the treatment of various psychiatric diseases is growing. OXT and AVP systems that exist in balance produce the contrary effect on emotional behaviour. Positive social stimuli and/or psychopharmacotherapy can shift this balance towards OXT and can help to stimulate emotional behaviour and restore mental health through this shifting. OXT produces an effect on several neurobiological systems, including the HPA axis, limbic system, neurotransmitters, and immune processes related to stress disorders. The exact effects of iOXT still remain unclear; nevertheless, it is known that iOXT action depends on individual sensitivity. Data from functional magnetic resonance imaging demonstrated that iOXT induces temporary activation of some cortex areas and prolonged activation of hippocampus and forebrain areas. These structures are characterized by a high density of OXT receptors. At the same time, iAVP causes stable deactivation in the parietal cortex, thalamus, and mesolimbic pathway. Importantly, the intravenous administration of OXT and AVP does not repeat activation patterns caused by intranasal administration of OXT and AVP. Nevertheless, it is possible that a small amount of OXT which crosses the blood-brain barrier may lead to an additional central OXT release since OXT is able to bind to brain OXT ergic neurons and cause its own release. Generally, OXT doses administered in studies vary from 15 IU to more than 7000 IU. As the table indicates, the results of these studies are very different. The most frequently used dose is 24 IU. Many studies are focused on the capability of OXT in the treatment of depressive disorders. It was demonstrated that iOXT reduces the time of concentration on aggressive facial expressions and increases the time of concentration on happy faces in men and women with chronic depression. Therefore, iOXT regulates emotion recognition in depression. iOXT can be used in combination with antidepressants, enhancing antidepressant efficiency. iOXT administration positively affects mother-child relationship in mothers with postpartum depression (PPD). iOXT activates the protective behaviour of mothers with PPD towards their children. Similar results were found in animal experiments. In rats, iOXT reduced the depressive-like behaviour in adult animals subjected to early maternal separation. Moreover, the research of specific neurogenesis markers Ki67 and BrdU demonstrated that iOXT promotes hippocampal neurogenesis, which is impaired in depressed rats. Many studies investigate the therapeutic properties of iOXT and iAVP for the treatment of schizophrenia and autism. It is known that schizophrenia disturbs social behaviour; and cognitive function. iOXT has the potential for usage as a therapeutic tool to restore impaired functions during schizophrenia. Some data suggest that iOXT reduces the negative symptoms of schizophrenia, improves working memory, verbal memory and cognitive function, and also improves social function in patients with schizophrenia and schizoaffective disorder. Although many studies indicate a positive effect of iOXT on cognitive function in people with schizophrenia, the neuropeptide has a very selective action on behaviour. The exact mechanism of iOXT action is also indefinite; therefore, its therapeutic potential requires further research. Eventually, iOXT can be used as an additional therapeutic agent in traditional schizophrenia treatment. iOXT can also be applied to ASD treatment. It was found that iOXT improves social abilities in children and emotionality in adult men with ASD. Moreover, the improvement of emotional state was observed in adults after an 8 IU dose, but not after 24 IU. The study of iOXT's therapeutic properties was also carried out using a mouse valproate autism model. iOXT improved social behaviour in that model, and reduced anxiety, depressive-like behaviour, and repetitive behaviour. iOXT has some positive effects in the ASD treatment. Despite this, studies of the potential therapeutic usage of iOXT are still at an early stage, and doctors have insufficient data to prescribe iOXT to patients. A few data indicate the therapeutic possibilities of AVP compared to OXT. It is known that iAVP was used in the treatment of the first episode of schizophrenia, in addition to the traditional benzodiazepine treatment. Cognitive functions (namely the memorization process, long-term and short-term memory) improved in patients. iAVP treatment ameliorated social ability in children with ASD. Additionally, iAVP treatment reduced anxiety and repetitive behaviors in these children. These data indicate the necessity of further investigation of AVP's treatment potential.

 

 

Rescue of oxytocin response and social behaviour in a mouse model of autism

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4-6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions. 

Social recognition and communication are crucial elements in the establishment and maintenance of social relationships. Oxytocin and vasopressin are two evolutionarily conserved neuropeptides with important functions in the control of social behaviours, in particular pair-bonding and social recognition7,8 . In humans, genetic variation of the oxytocin receptor (OXTR) gene is linked to individual differences in social behaviour9 . Consequently, signalling modulators and biomarkers for the oxytocin or vasopressin system are being explored for conditions with altered social interactions such as autism spectrum disorders (ASDs)5,6 . In mice, mutation of the genes encoding oxytocin or its receptor results in a loss of social recognition and social reward signalling10–14. Mutation of Cntnap2, a gene linked to ASD in humans, resulted in reduced levels of oxytocin in mice, and the addition of oxytocin improved social behaviour in this model15. However, the vast majority of genetic risk factors for autism have no known links to oxytocinergic signalling. 

Thus, modification of translation homeostasis in Nlgn3KO mice by MNK inhibition restores oxytocin responses and social novelty responses. This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses. Although loss of Nlgn3 impairs oxytocin responses in VTA DA neurons, the behavioural phenotype does not fully phenocopy genetic loss of oxytocin. Oxytocin knockout mice exhibit impaired habituation in the social recognition task10, whereas Nlgn3KO mice habituate normally but exhibit a selective deficit in the response to a novel conspecific. This is probably due to differential roles of Nlgn3 and oxytocin across several neural circuits and over development. Moreover, Nlgn3 loss-of-function also affects signalling through additional GPCRs23. We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis. Notably, MNK loss-of-function appears to be overall well tolerated. MNK1/2 double-knockout mice are viable46 and several MNK inhibitors are entering clinical trials for cancer therapy47. Previously available MNK inhibitors were greatly limited by specificity and brain penetrance. Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome41 to a non-syndromic model of ASD. The common disruption in translational machinery and phenotypic rescue in two very different genetic models indicate that genetic heterogeneity of ASD might be reduced to a smaller number of cellular core processes. This raises the possibility that pharmacological interventions targeting such core processes may benefit broader subsets of patient populations.

 

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice 

Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

  

Conclusion

I think I have written enough about Oxytocin and Vasopressin.

The research is not entirely consistent regarding Vasopressin, but my assumption is that for my kind of autism I want an Oxytocin Agonist and a Vasopressin Agonist, some people might think it would be a Vasopressin Antagonist.

The good news is that there is significant research in humans, reported in previous posts, to support the use of both Oxytocin Agonist and a Vasopressin Agonist

I also think there will be both short-term, or immediate effects, from both treatments but also potentially different long-term effects from continued therapy, that is indeed suggested by the animal research models.  For example, neurite outgrowth is stimulated by oxytocin.  It is suggested that oxytocin may contribute to the regulation of scaffolding proteins expression.


Is it worth using oxytocin as a therapy to generate some extra hugs? You can argue both ways, but the longer-term benefits of correcting low oxytocin levels may be more profound.

The effects of vasopressin and oxytocin are somewhat overlapping. We know that low levels of vasopressin in spinal fluid are a good marker for autism, so putting a little extra vasopressin in the brain does not seem unreasonable.

As usual with the human body, the effects of oxytocin and vasopressin are different within the brain and in the rest of your body.  Also, the levels of these hormones in your blood are not a good predictor of their levels within the brain.  This is a reoccurring problem.  Because taking a spinal fluid sample is an invasive procedure, it is rarely taking place and then endless time and money is wasted on blood tests that may well send the doctor in the wrong direction, or just no direction.

It is highly likely that increasing Oxytocin and Vasopressin in the brain is going to affect aggressive behaviors, via actions in the Lateral Septum (LS).  Due to the role of GABA potentiating activity in the Lateral Septum (LS) you might expect a possible difference in bumetanide-responders and bumetanide non-responders (because GABA is acting as excitatory).

I would consider Oxytocin and Vasopressin as fine-tuning autistic behavior and you would have to personalize the dosage. In some people it might be a case of either or, rather than both.

Using MNK inhibitors to treat human Fragile-X looks a great idea and hopefully a commercialized therapy could then be trialed in broader autism.

 



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.