6 replies to this topic

[nootist]

The following post is only about halfway complete.  It will be added to later, and updated from time to time.

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This thread is meant to give an introduction to what is known of the neurochenistry of autism, with particular focus on the unusual balance found between GABA and glutamate.  Other aspects may be covered in future threads.

Autism is not one thing, it is a collection of conditions which have some similarities, but over a thousand genes have been implicated as possibly involved, so what is true of one autistic person may be quite inapplicable to another.  The broader autism phenotype includes autism as identified by Kanner and Asperger, as well as ADHD, OCD and tic disorders, which frequently overlap with autism.  All of these show ties to GABA/glutamate dysregulation, often involving SLC1A1/EAAC1 glutamate transport, leading to excess glutamate^18,20. Epilepsy is also common among autistic people, affecting somewhere between 15 and 35 percent.  High levels of glutamate are also implicated in most forms of epilepsy.  Now for the technical breakdown.

Hyperglutamatergy is exhibited in the serum levels of more intelligent autistic children¹, autistic children in general², and autistic adults^3,15.  Excess glutamate is also found in the hippocampus and frontal lobes, striatum, anterior cingulate cortex/gyrus⁴, auditory cortex, and the cerebellum, which has led to successful use of antiglutamatergic drugs in treatment^5,6.  The glutamate/GABA imbalance is a possible cause of CNS inflammation and oxidative damage in autistics¹⁵.
 
Conversion of glutamate into GABA is often quite minimal, despite large numbers of GABA neurons in parts of the brain, as the receptors seem to be downregulated.  This appears to be linked to problems with GAD65 and GAD67, the two isoforms of glutamic acid decarboxylase, which convert glutamate into GABA¹⁷.  In the parietal and cerebellar cortexes of autistic people, GABA exists at only about half the levels found in neurotypicals⁵.  Low GABA has also been addressed in several successful treatments, including memantine, valproate, carbamazepine and arbaclofen^7,8,9,13,16.  These naturally counterbalance glutimate in the process.  Glycine inhibition has also been used successfully to control runaway glutamate in a knockout mouse model, although it caused behavioral anomalies in the control group, so was not tried with humans.¹⁰  In Rett Syndrome, which is (along with Fragile X) often considered close enough to autism to be a useful model, excessive glutamate is tied to SNAT1 glutamate transporter overexpression, with similar outcome^11.

While antagonizing glutamate and agonizing GABA are effective approaches^5,12, they are also blunt instruments.  Some initial attempts have been made to find and analyze the mGluRs involved, but the material's still pretty sketchy, and there's a lot left to be done.  mGluR group I (1,5) is looking like a trouble area¹⁷, and mGluR5 suppression with MPEP has worked in a knockout mouse model¹³, and can improve their memory as well as remedying other deficits¹⁴.

 

*********** To be continued ****************
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1. Alteration of Plasma Glutamate and Glutamine Levels in Children with High-Functioning Autism.  http://journals.plos...al.pone.0025340
2. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity.  http://www.biomedcen...3-7075-8-34.pdf
3. Increased serum levels of glutamate in adult patients with autism.  http://www.sciencedi...278584606002697
4. Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders.  http://www.ncbi.nlm....pubmed/25919578
5. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment.  http://www.ncbi.nlm....les/PMC4134390/
6. A Review on GABA/Glutamate Pathway for Therapeutic Intervention of ASD and ADHD.  http://www.ncbi.nlm....pubmed/25666800
7. Mood Stabilizers in Children and Adolescents With Autism Spectrum Disorders.  http://www.ncbi.nlm....pubmed/26366961
8.R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome. http://www.ncbi.nlm....pubmed/25820841
9. Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice. http://www.ncbi.nlm....pubmed/25662838
10.Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism.  http://www.ncbi.nlm....pubmed/25784602
11. Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.  http://www.jneurosci.../35/6/2516.long
12. A Review on GABA/Glutamate Pathway for Therapeutic Intervention of ASD and ADHD. http://www.ncbi.nlm....pubmed/25666800
13. Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.  http://www.ncbi.nlm....pubmed/25622145
14. Enhancement of Short-Term Memory by Methyl-6-(Phenylethynyl)-Pyridine in the BTBR T+tf/J Mouse Model of Autism Spectrum Disorder.  http://www.ncbi.nlm....les/PMC4384677/
15. GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders.  http://www.ncbi.nlm....les/PMC4243332/
16. A Review of Traditional and Novel Treatments for Seizures in Autism Spectrum Disorder: Findings from a Systematic Review and Expert Panel.  http://www.ncbi.nlm....les/PMC3859980/
17. Consensus Paper: Pathological Role of the Cerebellum in Autism.  http://www.ncbi.nlm....les/PMC3677555/
18. Family-Based Association Testing of OCD-Associated SNPs of SLC1A1 in an Autism Sample.  http://www.ncbi.nlm....les/PMC2688703/
19. Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder. http://www.ncbi.nlm....les/PMC3669922/
20. Brief Report: Glutamate Transporter Gene (SLC1A1) Single Nucleotide Polymorphism (rs301430) and Repetitive Behaviors and Anxiety in Children with Autism Spectrum Disorder.  http://www.ncbi.nlm....les/PMC4348063/

Edited by nootist, 24 September 2015 - 06:06 AM.

[Ark]

http://www.scienceda...medium=facebook

[gamesguru]

http://www.scienceda...medium=facebook

 

"spontaneous rare mutations cause half of autism"
fcking hell, no wonder moms are looking to blame vaccines

 

The interaction between GABA and dopamine: implications for schizophrenia.
D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus
Evidence That Sleep Deprivation Downregulates D2 in Ventral Striatum of Human Brain

Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors

[Area-1255]

 

http://www.scienceda...medium=facebook

 

"spontaneous rare mutations cause half of autism"
fcking hell, no wonder moms are looking to blame vaccines

 

The interaction between GABA and dopamine: implications for schizophrenia.
D2 receptor-mediated inhibition of GABA release by endogenous dopamine in the rat globus pallidus
Evidence That Sleep Deprivation Downregulates D2 in Ventral Striatum of Human Brain

Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors

 

Hahaha, Mercury and Copper plays as role too.

http://treatautism.c...n/heavy-metals/

 

 

Inhibition of GABA is not always a bad thing , though...as too much GABA tends to cause a lot of other issues - like lethargy, behavioral changes; disinhibition, stimulant addiction etc...however, too little GABA is a much more 'common' issue...and also contributes to neurotoxicity and mania/bipolar as well as epilepsy, acute stress induced psychosis and many other behavioral spectrums...oppositional defiance disorder seems to be related to low GABA as well.

 

http://www.ncbi.nlm....les/PMC3970207/

http://www.scielo.br...arttext&tlng=en

[nootist]

http://www.scienceda...medium=facebook

 

Great article!  The people I know best who are on the spectrum, aren't like that at all.  Their story starts out at least 95 years ago, when one of them was born with severe OCD.  That person had a kid with OCD, ADHD, and a seizure disorder, who in turn had a kid with OCD, hyperlexia, a seizure disorder, and a tic disorder as an adolescent.  When the latter grew up, they had two kids, both of whom are hyperlexic and autistic.  Whether it goes back more than four generations is unknown, but its 'de novo' days were around the outbreak of WWI, if not before.  Having autistic kids crop up in that family is no surprise at all, they could have been one of Dr. Asperger's original case studies.  But when it shows up in families where all other members are neurotypical, it's confusing, and people end up grasping at straws, like anti-vax theories.  Clarifying the issues, like that article does, is much needed.

 

Since autistic people who are unrelated can't be expected to have much in common, whether one is talking about genetics, environment, or anything else, I'm not going to try to tackle more than glu/GABA issues in this thread, but hope to eventually get around to unusual metabolism of methylation vitamins, and other issues that seem to apply to a large percentage of people on the spectrum.

 

I can no longer edit my original post, but will add to it with another post on mGluRs shortly.  It's going to be messy, though.  The studies are few, and small, and don't always agree with each other.  Having countless variations on the broader phenotype, really does not help.  There doesn't seem to be a single answer to much of anything in this field.

Edited by nootist, 24 September 2015 - 06:27 PM.

[Junk Master]

As a father of a teenager who is on the spectrum and high functioning; and, also has night time epilepsy thanks for your post.  A very promising beginning.

[Area-1255]

Also, pyroluria seems to be a condition that may affect the pathogenesis of ASD's and the presentation/severity of symptoms, at the least.

Only problem I have with the GABA/Glutamate discussion in relation to Austism - is that these are only two transmitters and most likely play a bigger role in again, the 'presentation' and severity of symptoms - as opposed to the unique etiologies which often occur AT BIRTH - and have several genomic , macrophysiological and intracellular factors . All of them together, set the STAGE for autism but we have to remember that  Autism is another disorder which can be characterized by a SHIFT in the logical/intellectual portion of the brain VERSUS the emotional connections. Exposure to various sex hormones at birth may influence this as well. There have also been studies showing that estrogen exposure as in synthetic estrogen and / or high plasma testosterone in the mothers blood during pregnancy may affect the outcome and ultimately the likelihood of ASD's and other conforming deficits to occur. 

 

REMEMBER these are CORE structural abnormalties in the brain though - not merely a 'chemical imbalance' but something much higher at play which involves entire neuronal networks - even so extending to the brain stem or entire frontal lobe.

 

Which brings me to my next point - in that there IS huge parallel between OCD, AntiSocial Personality and Autism - which all can be seen as 'like disorders' with similar pathologies. Obsessive-Compulsives often appear emotionally shallow (although sometimes it is the opposite e.g over - dramatic) because their mind IS wandering however they do often experience emotional deficits - if not a result of their brain wiring then as a result of SSRI's they are often put on. 

 

ASP; which is a precursor to psychopathy - is characterized by lack of empathy, shallower emotions, disregard for the law and excessive grandiosity as well as blaming others for their mistakes...this is also on the same 'spectrum' and there are A LOT of parallel's between Autistics and those affected with ASP.

 

Though, Autistics don't frequently turn violent - at least not with specific intent as those with ASP may be predisposed to ...

Of course, the same can be said about obsessive-compulsives, that they are almost never violent and generally have a 'good conscience' and strong moral obligations...the question is WHEN/WHERE the line is crossed to 'projection and polarization' which is where it is no longer strictly moral amplitude but now black and white thinking where one has such disgust for their pet-peeves or moral nemesis that they 'take matters into their own hands'...obviously is indicative of both over-expressed emotions and yet under-expressed in terms of empathy or WHOLE-PICTURE evaluation... 

 

Thus there are certainly, core structural abnormalties though OCD subjects usually don't lack oxygen distribution as those with ASP do - and those with severe psychopathy tend to have very low heart rates... but interestingly and now coming back to this all again..heavy metals play a role in (perhaps not coincidentally) ALL THREE of those disorders ; OCD, ASP AND ASD's/Asperger's. 

 

The pathological/psychological EXPRESSION of such disorders makes each of them hard to distinguish at first glance..and even under periods of intense evaluation EVEN IN A MEDICAL SETTING these disorders are very difficult to tell apart...particularly depending on the subjects level of exposure to communication and their age and interpretive abilities. 

 

 

http://equilibriumna...-abnormalities/

http://therivertorec....com/pyroluria/

http://evolutionaryp...ldren-with.html

http://community.bab...tistic_children

 

 

PLoS One. 2013 Sep 25;8(9):e74849. doi: 10.1371/journal.pone.0074849. eCollection 2013.

Mothers of autistic children: lower plasma levels of oxytocin and Arg-vasopressin and a higher level of testosterone.

Xu XJ1, Shou XJ, Li J, Jia MX, Zhang JS, Guo Y, Wei QY, Zhang XT, Han SP, Zhang R, Han JS.

Author information

 

Abstract

BACKGROUND:

Autism is a pervasive neurodevelopmental disorder,thought to be caused by a combination of genetic heritability and environmental risk factors. Some autistic-like traits have been reported in mothers of autistic children. We hypothesized that dysregulation of oxytocin (OXT), Arg-vasopressin (AVP) and sex hormones, found in autistic children, may also exist in their mothers.

METHODS:

We determined plasma levels of OXT (40 in autism vs. 26 in control group), AVP (40 vs. 17) and sex hormones (61 vs. 47) in mothers of autistic and normal children by enzyme immunoassay and radioimmunoassay, respectively and investigated their relationships with the children's autistic behavior scores (Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC)).

RESULTS:

Significantly lower plasma concentrations of OXT (p<0.001) and AVP (p<0.001), as well as a higher level of plasma testosterone (p<0.05), were found in mothers of autistic children vs. those of control. The children's autistic behavior scores were negatively associated with maternal plasma levels of OXT and AVP.

CONCLUSIONS:

These results suggest that dysregulation of OXT, AVP and/or testosterone systems exist in mothers of autistic children, which may impact children's susceptibility to autism.

PMID:   24086383   [PubMed - indexed for MEDLINE]    PMCID:   PMC3783493     Free PMC Article