Showing posts with label pH. Show all posts
Showing posts with label pH. Show all posts

Tuesday 23 April 2024

Maternal Agmatine or Choline to prevent autism? International brain pH project. Androgen levels in autism spectrum disorders. Apigenin works for BTBR mice. Auditory hypersensitivity, myelin and Nav1.2 channels. Dopamine transporter binding abnormalities and self-injury


Shutting the stable door after the horse has bolted

Today’s post is a summary of what I found interesting in the latest research.  Many items have been touched on previously.

The topic of maternal treatment to prevent future autism did come up in some recent comments on this blog. Two of the recent papers cover this very subject. One uses agmatine, from my autism PolyPill therapy, while the other used choline.

Auditory sound sensitivity is a complex subject and today we see the potential role impaired myelination and Nav1.2 ion channels can play.

A Chinese study reconfirms the elevated level of androgen hormones in autism.  

Apigenin which was covered in an earlier post is shown to help “autistic” mice in the popular BTBR model. This is a model where the corpus callosum is entirely absent.

Self-injury is a recuring nightmare for many with severe autism and today we look at a possible correlation with dopamine transporter binding abnormalities.

We start with easier subject matter and leave the hard parts for later in the post.

Preventing future autism

It may seem like too late to be talking about preventing autism, but it is a recurring subject. Today we have two new ideas that have appeared in the literature, and both are very simple. One is choline and other agmatine; both are used in the treatment of already existing autism.


Maternal choline to prevent autism

“maternal choline supplementation may be sufficient to blunt some of the behavioral and neurobiological impacts of inflammatory exposures in utero, indicating that it may be a cheap, safe, and effective intervention for neurodevelopmental disorders.” 


Maternal choline supplementation modulates cognition and induces anti-inflammatory signaling in the prefrontal cortex of adolescent rats exposed to maternal immune activation

Maternal infection has long been described as a risk factor for neurodevelopmental disorders, especially autism spectrum disorders (ASD) and schizophrenia. Although many pathogens do not cross the placenta and infect the developing fetus directly, the maternal immune response to them is sufficient to alter fetal neurodevelopment, a phenomenon termed maternal immune activation (MIA). Low maternal choline is also a risk factor for neurodevelopmental disorders, and most pregnant people do not receive enough of it. In addition to its role in neurodevelopment, choline is capable of inducing anti-inflammatory signaling through a nicotinic pathway. Therefore, it was hypothesized that maternal choline supplementation would blunt the neurodevelopmental impact of MIA in offspring through long- term instigation of cholinergic anti-inflammatory signaling.

To model MIA in rats, the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) was used to elicit a maternal antiviral innate immune response in dams both with and without choline supplementation. Offspring were reared to both early and late adolescent stages (postnatal days 28 and 50, respectively), where cognition and anxiety-related behaviors were examined. After behavioral testing, animals were euthanized, and their prefrontal cortices (PFCs) were collected for analysis. MIA offspring demonstrated sex-specific patterns of altered cognition and repetitive behaviors, which were modulated by maternal choline supplementation. Choline supplementation also bolstered anti-inflammatory signaling in the PFCs of MIA animals at both early and late adolescent stages. These findings suggest that maternal choline supplementation may be sufficient to blunt some of the behavioral and neurobiological impacts of inflammatory exposures in utero, indicating that it may be a cheap, safe, and effective intervention for neurodevelopmental disorders.


Prenatal Agmatine to prevent autism

Agmatine is a cheap bodybuilder supplement also used in psychiatry that has been extensively covered in this blog. Here we see how in a popular mouse model it can prevent autism.

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway

Background: According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid.

Methods: In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring.

Results: The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway.

Conclusion: Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

This builds on an earlier paper that first identified the benefit.


Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism



                  Single treatment of agmatine rescues social impairment in the VPA-induced animal model of autism.

                  Effect of agmatine in social improvement in the VPA model is induced from agmatine itself, not its metabolite.

                  Agmatine rescues repetitive and hyperactive behavior, and seizure susceptibility in the VPA model.

                  Overly activated ERK1/2 in the brain of the VPA model is relieved by agmatine.



50mg of Apigenin

1g of dried parsley
15-20g of dried chamomile flowers


I have previously written about Apigenin, which is an OTC supplement. There has been another paper recently published about it. There is a logical connection with the maternal choline therapy from above.


What does Apigenin have in common with Choline?  α7-nAChRs

Choline is interesting because it acts as both a precursor for acetylcholine synthesis and it is a neuromodulator itself.

Choline is activates α7-nAChRs, alpha-7 nicotinic acetylcholine receptors.

These receptors are extremely important in learning and sensory processing.  They also play a key role in inflammation and signaling via the vagus nerve.

Apigenin is a flavonoid found in many plants, fruits, and vegetables. It has been shown to have a number of health benefits, including anti-inflammatory and antioxidant effects. Apigenin has also been shown to interact with α7-nAChRs.

Studies have shown that apigenin can:

Enhance α7-nAChR function: Apigenin has been shown to increase the activity of α7-nAChRs. This may be due to its ability to bind to a specific site on the receptor.

Protect α7-nAChRs from damage: Apigenin may also help to protect α7-nAChRs from damage caused by oxidative stress.


Apigenin Alleviates Autistic-like Stereotyped Repetitive Behaviors and Mitigates Brain Oxidative Stress in Mice

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10–30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10–30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD.


Altered acidity (pH) levels inside the brain

I found it intriguing that a large study has examined the altered acidity (pH) levels inside the brain of those with neurological disorders.

For all the disorders other than autism there was a clear pattern of low pH, which means increased acidity.

For autism certain autism models exhibited decreased pH and increased lactate levels, but others showed the opposite pattern, reflecting subpopulations within autism.

Altered brain energy metabolism is an acknowledged feature of autism, so we should not be surprised to find altered levels of acidity.

The easy reading version:


Brain Acidity Linked With Multiple Neurological Disorders


The study itself:

Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

In conclusion, the present study demonstrated that altered brain pH and lactate levels are commonly observed in animal models of SZ, BD, ID, ASD, AD, and other neuropsychiatric disorders. These findings provide further evidence supporting the hypothesis that altered brain pH and lactate levels are not mere artifacts, such as those resulting from medication confounding, but are rather involved in the underlying pathophysiology of some patients with neuropsychiatric disorders. Altered brain energy metabolism or neural hyper- or hypoactivity leading to abnormal lactate levels and pH may serve as a potential therapeutic targets for neuropsychiatric disorders


Why would the brain be acidic (reduced pH)?

To function optimally mitochondria need adequate oxygen and glucose. When performance is impaired, for example due to the lack of Complex 1, mitochondria switch from OXPHOS (oxidative phosphorylation) to fermentation to produce energy (ATP). Lactic acid is the byproduct and this will lower pH.


Does brain pH matter?

It does matter and is linked to cognitive impairments, headaches, seizures etc.

Many enzymes in the brain rely on a specific pH range to function properly. Deviations from the ideal pH can hinder their activity, impacting various neurochemical processes essential for brain function.

Some ion channels are pH sensitive.


Chemical buffers in the brain aim to regulate pH in the brain

·       Carbonic Acid/Bicarbonate Buffer System: Similar to the blood, the brain utilizes this system to regulate pH.

·   Organic Phosphates: These molecules, like creatine phosphate, can act as buffers in the brain by binding or releasing hydrogen ions.

These buffering systems work together to maintain a tightly controlled pH range in both the blood (around 7.35-7.45) and the brain (slightly more acidic than blood, around 7.0-7.3). Even slight deviations from this ideal range can have significant consequences for cellular function.


Androgen Levels in Autism

Androgens are male hormones like testosterone, DHEA and DHT, but females have them too, just at lower levels.

Drugs that reduce the level of these hormones are called antiandrogens.

Finasteride reduces DHT and is used to treat hair loss in men as Propecia. This drug was trialed in women, but failed to show a benefit over the placebo.

The main use of Finasteride is for the treatment of benign prostatic hyperplasia (BPH) in older men.

Women sometimes take antiandrogens like Spironolactone to control acne.

Numerous studies have show elevated levels of males hormones in both males and females with autism.

A recent paper was published on this very subject: 

Androgen levels in autism spectrum disorders: A systematic review and meta-analysis


Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls.


A systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I 2 statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity.


17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06-0.48, P=0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD. Androgen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males.


By coincidence I was just sent the paper below, showing the benefit of Finasteride in one model of autism. 

Therapeutic effect of finasteride through its antiandrogenic and antioxidant role in a propionic acid-induced autism model: Demonstrated by behavioral tests, histological findings and MR spectroscopy


I do recall I think it was Tyler, long ago, writing a comment about the potential to use Finasteride in autism.

Some very expensive antiandrogens have been used in autism and this became rather controversial.

We saw in earlier posts that RORα/RORalpha/RORA is a key mechanism where the balance between male and female hormones controls some key autism gene.


The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.

 androgen receptor = AR             estrogen receptor = ER

Cerebellum and neurodevelopmental disorders: RORα is a unifying force

Errors of cerebellar development are increasingly acknowledged as risk factors for neuro-developmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. Evidence has been assembled from cerebellar abnormalities in autistic patients, as well as a range of genetic mutations identified in human patients that affect the cerebellar circuit, particularly Purkinje cells, and are associated with deficits of motor function, learning and social behavior; traits that are commonly associated with autism and schizophrenia. However, NDDs, such as ASD and schizophrenia, also include systemic abnormalities, e.g., chronic inflammation, abnormal circadian rhythms etc., which cannot be explained by lesions that only affect the cerebellum. Here we bring together phenotypic, circuit and structural evidence supporting the contribution of cerebellar dysfunction in NDDs and propose that the transcription factor Retinoid-related Orphan Receptor alpha (RORα) provides the missing link underlying both cerebellar and systemic abnormalities observed in NDDs. We present the role of RORα in cerebellar development and how the abnormalities that occur due to RORα deficiency could explain NDD symptoms. We then focus on how RORα is linked to NDDs, particularly ASD and schizophrenia, and how its diverse extra-cerebral actions can explain the systemic components of these diseases. Finally, we discuss how RORα-deficiency is likely a driving force for NDDs through its induction of cerebellar developmental defects, which in turn affect downstream targets, and its regulation of extracerebral systems, such as inflammation, circadian rhythms, and sexual dimorphism.


Figure 2. RORα regulates multiple genes and plays extensive roles in cerebellar development. (A) Key stages of PC development which are regulated by RORα. These are at all stages from embryonic development to adult maintenance. (B) A schema showing the central role of RORα in multiple cellular processes, that are modified in NDDs. When RORα is reduced (central red circle), its regulation of gene transcription is altered. Here we include the known RORα target genes that are also involved in NDDs. The effects in red illustrate the induced abnormalities according to the direction of change: estrogen and PC development are reduced, circadian rhythms are perturbed, but inflammation and ROS are increased.


Sound sensitivity in autism and Nav1.2

At this point today’s post does get complicated.

Researchers have learnt that the sodium ion channel Nav1.2 (expressed by the SCN2A gene) can play a key role in hypersensitivity to sound in autism.

Lack of these ion channels in the cells that produce myelin produces “faulty auditory circuits”, with too much sound sensitivity.

An impairment in myelin structure can trigger cascading effects on neuronal excitability. Sound sensitivity is just one example.

There is a great deal of evidence that genes involved in myelination are miss-expressed in many models of autism. Imaging studies have shown variations in myelination.


Scn2a deletion disrupts oligodendroglia function: Implication for myelination, neural circuitry, and auditory hypersensitivity in ASD

Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the Scn2a gene emerges as a pivotal player, crucially involved in both glial and neuronal functionality. This study elucidates the underexplored roles of Scn2a in oligodendrocytes, and its subsequent impact on myelination and auditory neural processes. The results reveal a nuanced interplay between oligodendrocytes and axons, where Scn2a deletion causes alterations in the intricate process of myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, oligodendrocyte-specific Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity—a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered by Scn2a deletion. In summary, the findings provide unprecedented insights into the pathway from Scn2a deletion in oligodendrocytes to sensory abnormalities in ASD, underscoring the integral role of Scn2a-mediated myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.

Therefore, our study underscores the region-specific relationship between myelin integrity and ion channel distribution in the developing brain. We emphasize that any disturbances in myelin structure can trigger cascading effects on neuronal excitability and synaptic function in the CNS, especially at nerve terminals in the auditory nervous system. 

How are Nav1.2  channels, encoded by Scn2a, involved in OL maturation and myelination? One possible explanation is that the activation of Nav1.2 may be pivotal for triggering Cav channel activation, leading to a Ca2+ flux within OLs, which is involved in OL proliferation, migration, and differentiation. Specifically, Ca2+ signaling facilitated by R-type Cav in myelin sheaths at paranodal regions, might influence the growth of myelin sheaths. To activate high-voltage activated calcium channels such as L- and R-Type efficiently, the activation of Nav1.2 channels should be required for depolarizing OL membrane to around -30 mV. Consequently, the synergic interplay between Nav1.2 and Cav channels could amplify calcium signaling in OLs, initiating the differentiation and maturation processes. 

Defects in myelination can create a spectrum of auditory dysfunctions, including hypersensitivity. Our results demonstrated how OL-Scn2a is involved in the relationship between myelin defects, neuronal excitability, and auditory pathology in ASD, potentially paving the way for targeted therapeutic interventions.


One subject that some people write to me repeatedly about is self-injurious behavior, so I took note of the paper below.  

Dopamine Transporter Binding Abnormalities Are Associated with Self-injurious Behavior in Autism Spectrum Disorder 

Utilizing single-photon emission computed tomography dopamine transporter scans (DaTscan) we examined whether imaging markers of the dopaminergic system are related to repetitive behaviors as assessed by the Repetitive Behavior Scale-Revised in ASD.


Autism spectrum disorder (ASD) is characterized by impairments in social communication, and restricted repetitive behaviors. Self-injurious behaviors are often observed in individuals with ASD. Dopamine is critical in reward, memory, and motor control. Some propose the nigrostriatal motor pathway may be altered in ASD, and alterations in dopamine are reported in some rodent models based on specific ASD genes. Additionally, repetitive behaviors may to be related to reward systems. Therefore, we examined the dopaminergic system, using DaTscans, to explore its relationship with measures of repetitive behavior in a clinical ASD population.


Twelve participants (aged 18–27) with ASD were recruited from the Thompson Center for Autism and Neurodevelopment and completed the Repetitive Behaviors Scale - Revised (RBS-R). Of the 12 participants, 10 underwent a 45-minute DaTscan. ANOVA was used to compare the dopamine imaging findings with the overall total RB scores on the RBS-R. while other domains of the RBS-R were also investigated in an exploratory manner.


Five of the participants had regional deficits in dopamine transporter binding in the striatum on DaTscan. Individuals with deficits on the DaTscan had significantly higher Self-Injurious Endorsed Scores than those with normal scans.


Half of the DaTscans obtained were determined abnormal, and abnormal scans were associated with greater endorsing of self-injurious behavior. Larger samples are needed to confirm this, and determine the impact of laterality of abnormalities, but this preliminary work suggests a potential role the dopaminergic system in self-injurious RBs. Elucidation of this relationship may be important for future interventional outcomes, with potential impact on targeted treatment, as the only currently approved medications for ASD are atypical neuroleptics.


Dopamine transporter binding abnormalities refer to deviations from the normal levels of dopamine transporter (DAT) in the brain. DAT is a protein on the surface of cells that reabsorbs dopamine from the synapse, regulating its availability.

Imaging techniques like DAT scans (dopamine transporter scans) are used to assess DAT levels. These scans measure the binding of radiotracers to DAT, with lower binding indicating reduced DAT levels.

Dopamine transporter binding abnormalities have been linked to various neurological and psychiatric conditions, including:

                 Parkinson's disease: Degeneration of dopamine-producing neurons in the substantia nigra, a hallmark of Parkinson's disease, leads to a significant decrease in dopamine levels and DAT binding in the striatum.

                 Attention deficit hyperactivity disorder (ADHD): Some studies suggest that individuals with ADHD may have abnormal DAT function, though the nature of the abnormality (increased or decreased DAT) is debated.

                 Autism spectrum disorder (ASD): Research suggests that a subgroup of individuals with ASD may have DAT abnormalities, potentially linked to repetitive behaviors and social difficulties.

                 Addiction: Dopamine plays a central role in reward and motivation. Drugs like cocaine and methamphetamine can cause long-term changes in DAT function, potentially contributing to addiction.

DAT binding abnormalities may not always translate to functional impairments.


Treatment options for DAT binding abnormalities

Unfortunately, medications that directly target Dopamine Transporter (DAT) binding abnormalities do not exist.

In Parkinson's disease the goal is to increase dopamine levels in the brain. Medications like levodopa, a dopamine precursor, or dopamine agonists (drugs that mimic dopamine) are used.



It certainly is not easy to figure out how to treat autism and its troubling symptoms like self-injury. Our reader currently trying to make sure his second child does not have severe autism is wise to invest his time now.

Today we added agmatine and choline to our list of preventative strategies to consider.

As regards strategies to treat autism in children and adults, we see that the research very often is repeating what has already been published over the past two decades.

Ion channels do seem to be central to understanding and treating autism.

Wednesday 30 August 2017

Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.
NSAIDs like ibuprofen are inhibitors of ASICs.
The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca2+ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.
Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.
ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca2+permeability and an inward flow of Ca2+. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.
However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.
A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.
“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Role of ASICs
Parkinson’s disease
Lactic acidosis occurs in the brains of patients with PD.
Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease
ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia
Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Most dural afferent nerves express ASICs.
Multiple sclerosis
ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma
ASIC1a is widely expressed in malignant glial cells.
PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 
One theory is that panic attacks are cause by too much lactic acid.
In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.
So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.
So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?
Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.
So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Acid sensing ion channels (ASICs) generate H+-gated Na+ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.
These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO3 or H+ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca2+]i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy
As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine
In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.
The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.
Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.
However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  
So nothing is clear cut.
It looks like spermine, spermidine and agmatine all promote autophagy.            
Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.
Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 
If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.
I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.
If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.
It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.
One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.
Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.
Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.
Science has a long way to go before there is a complete understanding of this subject.
Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).