Showing posts with label E/I balance. Show all posts
Showing posts with label E/I balance. Show all posts

Friday, 8 June 2018

Critical Periods in the Biology of Autism – Not to miss the Boat

This blog has shown that great things are possible just by fine-tuning a full-sized autistic brain, during childhood. In the case of our reader Roger, we are reminded that in adulthood the correct intervention can have profound results.

It is never too late.

Nonetheless, it is clear that the sooner you intervene with biology, the better the end result should be.
There is a concept of Critical Periods (also called sensitive periods) where it seems the maturation of a young brain is particularly vulnerable to both environmental and genetic insults. During these periods if you intervene pharmacologically you might make permanent life-changing modifications to the brain.  The recurring theme in Critical Periods in autism is a disturbed excitatory-inhibitory (E/I) balance. This is the same E/I imbalance discussed in depth in this blog. 
Some conditions that may lead to autism are detected before birth, such as Down Syndrome (DS) and many others could be. Surprisingly, there is now an experimental DS therapy that commences prior to birth. 
Emerging tests, such as one using an EEG, can predict with some accuracy which babies will develop autism.

When is it too late?
I think it is never too late to intervene in the biology of autism, but the sooner you do so the more productive it will be.
The sequence of Critical Periods starts before birth, with gestational weeks 10–24, highlighted in one paper. Birth itself is a critical period, as discussed by Ben Ari. By 12 months the autistic brain has already measurably overgrown, but this process continues to three years old. One researcher, Knut Wittkowski, believes that a therapy given during the second year of life can redirect future severe autism towards an Asperger’s-like outcome.
After the age of six, critical brain development has mostly been completed, except for synaptic pruning that occurs gradually during adolescence.

Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits.

Figure 1: Possible critical period alterations in autism. The solid black curve represents the normal expression of a critical period, with a distinct onset and closure and characteristic duration. Onset could be precocious or delayed. Duration could be increased or decreased. Degree of plasticity could be increased or decreased. Finally, the critical period could fail to open or close.

The variable nature of E/I imbalance and altered plasticity in autism animal models suggests that the disruption of critical periods in autism is likely heterogeneous, in some cases resulting in excessive plasticity and in others, insufficient plasticity. This could be due to disruption of the mechanisms governing either the onset or closing of critical periods Figure 1, and both could be detrimental to functioning. A brain that is too plastic at the wrong times could result in noisy and unstable processing. On the other hand, a brain that lacks plasticity early in life might remain hyper- or hypoconnected and unresponsive to environmental changes early in life. A situation could also arise where plasticity is at an optimal level in some systems and an aberrant level in other systems, which could the case in Asperger and/or Savant syndrome.

Autism is diagnosed exclusively by cognitive behavioral symptoms, but there are likely underlying problems arising at lower-level stages of processing. By first understanding the development of primary senses in autism, a cumulative chain reaction of abnormalities could be prevented early on and save consequent behavior. In the long run, a collaborative multilevel analysis of different brain regions over development and in different animal models of autism is of paramount importance. Hypothesis-driven efforts may then have a wider implication for the diagnosis and treatment of neurodevelopmental disorders in general. We are now in the position to adopt a mouse model to human multi level analysis approach to test well-defined, mechanistic hypothesis and to discover new therapeutic interventions to restore normal cortical function.

Let us see what Ben-Ari has to say on this subject

Birth is associated with a neuroprotective, oxytocin-mediated abrupt excitatory-to-inhibitory GABA shift that is abolished in autism, and its restoration attenuates the disorder in offspring. In this Opinion article, I discuss the links between birth-related stressful mechanisms, persistent excitatory GABA actions, perturbed network oscillations and autism. I propose that birth (parturition) is a critical period that confirms, attenuates or aggravates the deleterious effects of intrauterine genetic or environmental insults.
Birth is associated with a neuroprotective, oxytocin-mediated abrupt excitatory-to-inhibitory GABA shift that is abolished in autism, and its restoration attenuates the disorder in offspring. In this Opinion article, I discuss the links between birth-related stressful mechanisms, persistent excitatory GABA actions, perturbed network oscillations and autism. I propose that birth (parturition) is a critical period that confirms, attenuates or aggravates the deleterious effects of intrauterine genetic or environmental insults.

Cerebellar research has focused principally on adult motor function. However, the cerebellum also maintains abundant connections with nonmotor brain regions throughout postnatal life. Here we review evidence that the cerebellum may guide the maturation of remote nonmotor neural circuitry and influence cognitive development, with a focus on its relationship with autism. Specific cerebellar zones influence neocortical substrates for social interaction, and we propose that sensitive-period disruption of such internal brain communication can account for autism’s key features.
Three recent computational studies have used aggregated gene expression patterns to ask when and where ASD genes are expressed. Some ASD susceptibility genes show a high degree of coexpression with one another in mouse and human brain, allowing the identification of specific gene networks or “cliques”. ASD-related coexpression networks have been found during two distinct periods of development. First, during human gestational weeks 10–24 and mouse postnatal days 0–10 (P0–P10), expression occurs in a broadly defined somato-motor-frontal region (especially in layer 5/6 cortical projection neurons  and other layers. Second, in humans from neonatal to age 6, cerebellar network expression is strong, particularly in the cerebellar granule cell layer
Taken together, these patterns identify two regions where genetically driven ASD-related developmental programs can go off track: the second-trimester frontal/somatomotor neocortex and the perinatal/postnatal cerebellar cortex. Based on gene ontology classification, many of the coexpressed ASD susceptibility genes are involved in synaptic plasticity, development, and neuronal differentiation, indicating disruptions in neural circuit formation and plasticity as targets for investigation.
Long-term compensation is unlikely only in cerebellar agenesis, in which motor function remains underdeveloped throughout life. Thus, the cerebellum is compensatable with respect to motor functions, but cognitive and social functions are specifically vulnerable to early-life perturbation of cerebellum—suggesting a sensitive-period mechanism.

In infants who later go on to develop autism, increased net brain growth is apparent by age 1, as quantified by increased head circumference. Extreme head growth is associated with the most severe clinical signs of autism. In volumetric MRI measurements, ASD brains grow faster on average than neurotypical brains in the first two postnatal years. By age 2.5, brain overgrowth is visible as enlargement of neocortical gray and white matter in frontal, temporal, and cingulate cortex. Since this abnormal growth comes after the time of neurogenesis, volume differences are likely to arise either from disruption of progressive (growth) or regressive (pruning) events. Disruption to either of these processes could account for perturbations in the trajectory of gross volume changes. Additional contributions could also come from changes in glial volume or number. Finally, overgrowth in ASD brains is followed by premature arrest of brain growth after age 4. These abnormalities would be expected from defects in plasticity mechanisms—for example, dendritic growth and pruning or axonal branching.

Such a deficit in sensitive-period circuit refinement could arise in two ways. First, inappropriate input, as originally described by Hubel and Wiesel, could fail to instruct developing circuitry through Hebbian plasticity mechanisms. This could occur if subcortical structures, including the cerebellum, were perturbed. For example, reduced numbers of Purkinje cells, which are inhibitory, could allow abnormally high levels of firing by deep-nuclear projection neurons. Second, plasticity mechanisms themselves could be perturbed by specific alleles of the genes that govern those mechanisms. Both cases amount to a failure of postnatal experience to have its normal effects on the neocortex. Such a failure could contribute to the blunting of regional differences in gene expression across neocortical regions that is seen in autistic subjects.

Sensitive Periods for Cognitive and Social Function

Higher sensory capabilities are thought to undergo sensitive periods once lower sensory structures have matured. A similar principle is likely to apply to cognitive functions. One illustrative example is the ontogeny of reading. In early readers, activated brain regions are distributed on both sides of the neocortex and cerebellum. Between childhood and adolescence, these regions come to exclude auditory regions, leaving a more focused, largely left-hemisphere network that includes the visual word form area. Notably, in readers who first learn to read as adults, activity patterns are more bilaterally distributed  and are reminiscent of literate children starting to read, indicating that adult circuitry has considerably less capacity for refinement

The chart below is interesting; be careful with baby's head during birth. 

Risk ratios for ASD for a variety of probable genetic (light blue) and environmental (dark blue) factors. Risk ratios were taken directly from the literature except for the largest four risks, which were calculated relative to the U.S. general-population risk. At 36×, cerebellar injury carries the largest single nonheritable risk. For explanation of other risks, see text.

Critical Periods and the Immune System  
There is more to Critical Periods than just an excitatory-inhibitory (E/I) imbalance. We have seen in earlier posts that the immune system needs to be "calibrated" very early in life. If this does not occur correctly, the baby grows up with an immune system that does not respond only to genuine threats, but is over-activated and attacks the healthy body; this results in auto-immune disease. Autism can in part be considered an auto-immune disease.   The critical period to calibrate your immune system is during pregnancy and in the first months of life.
This is why having a pet indoors during pregnancy reduces asthma rates in the child. Giving babies probiotics also has been shown to reduce immune conditions and also conditions like ADHD and milder autism.
Giving the same probiotics to older children does not have the disease-changing benefit; the Critical Period to set up the immune system has past. The only work around, shown effective in MS, is to reboot the immune system and start again, using a bone marrow transplant. 
A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial
Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.


At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.


Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.
Critical Period E/I Intervention
We already have mouse research showing how early intervention can achieve permanent disease-changing benefits as suggested in the above papers. The paper below concerns a model of Fragile-X.

Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.

Mefenamic Acid (Ponstan)
The other potentially disease changing therapy mentioned in this blog is Mefenamic Acid, which is available OTC in many countries as Ponstan. Knut Wittkowski, is developing his idea that the cascade of damaging events that occur in severe autism after birth can be reduced by Mefenamic Acid. He is proposing this as a medium term therapy, just until key stages in brain maturation have been completed.
In effect his idea is to shift a trajectory set to severe autism to one of mild autism.
We could call it a potential trajectory changing therapy.
His start-up company is called Asdera.

Asdera's Vision is to Prevent Mutism in Autism

Among the  more than 60,000 US children who develop autism spectrum disorders (ASD) every year, 20,000 become nonverbal and will have to rely on assisted living for the rest of their life. Genetics ( suggest that mutism is to autism what pneumonia is to the common cold – more severe than the underlying condition (“Asperger’s”), but easily treatable by an exceptionally safe drug given to high risk children during the 2nd year of life to prevent disruption of active language development (DALD) from causing life-long lack of language and intellectual disability”

The Mainstream view of the Critical Period in Autism 
Monty was diagnosed in 2006 with autism by a neurodevelopmental pediatrician; one thing she told us was that up until the age of 6, remarkable improvement is possible, in some people. She recommended applying PECS (Picture Exchange Communication System) and TEACCH, using speech therapists and occupational therapists and hope for the best.
The US and Canada are unusual in diagnosing autism at two years of age, more typical is the advice below from Hong Kong:-

Research has indicated that the golden treatment period for autism is between age 0 to age 6, because the development of cognitive, coordinative, sensory and social skills in children within that age group is the quickest.
Children who are suspected to be autistic should receive assessment before age 4 or 4.5. Once diagnosed with the disorder, the child should receive professional training which lasts for at least two years before primary one.

I find it encouraging how in the decade since my son was diagnosed with autism we have gone from finding partially-effective experimental therapies to now having some researchers thinking about the time dimension (longitudinally). When do you need to intervene to make the greatest impact and can you do this even before symptoms have manifested themselves?

Our English neurodevelopment paediatrician from 2006 might see this as a pipe dream, but the authors of today’s first paper from Boston Children’s Hospital are already thinking along the right lines.  

The only risk is that minor brain changes possibly caused by a disruption in the E/I balance probably do produce those highly intelligent Asperger’s types who function perfectly well.  If you identified their odd EEG at 3 months of age and intervened, you might produce a social, rather than nerdy child, but no longer quite as intelligent.
If you can avoid the 0.3% of children having severe autism, which is Knut’s objective, I think you would have done well.                                                                          
I would agree with Courchesne (the previous post about brain overgrowth in autism) that by the time most autism intervention start the autistic brain has already neared adult size; he rather suggests that by then it is game over, it clearly is not. You have not missed the boat, even intervening in adulthood, it is just that the final destination will be different. 

As regards prevention of future autism (and ADHD), buy a dog before starting a family and from birth add a mix of probiotic bacteria to the baby's diet.      

         Not a bad destination

Friday, 21 April 2017

The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R

This blog aims to synthesize the relevant parts of the research and make connections that point towards some potential therapeutic avenues.  Most researchers work in splendid isolation and concentrate on one extremely narrow area of interest.

The GABAA reset, not functional in some autism

On the one hand things are very simple, if the GABAA receptors function correctly and are inhibitory and the glutamate receptors (particularly NMDA and mGluRx) function correctly, there is harmony and a  perfect excitatory/inhibitory balance.

Unfortunately numerous different things can go wrong and you could write a book about each one.

As you dig deeper you see that the sub-unit make-up of GABAA receptors is not only critical but changes.  The plus side is that you can influence this.

Today we see that the receptors themselves are physically movable and sometimes get stuck in the “wrong place”. When the receptors cluster close together they produce a strong inhibitory effect, but continual activation of NMDA receptors by the neurotransmitter glutamate - as occurs naturally during learning and memory, or in epilepsy - leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA. There needs to be a mechanism to move the GABAA receptors back into their original clusters.

Very clever Japanese researchers have figured out the mechanism and to my surprise it involves one of those hubs, where strange things in autism seem to connect to, this time IP3R.

I guess the Japanese answer to my question above is simple. YES,

A very recent science-light article by Gargus on IP3:-

Now to the Japanese.

I wonder if Gargus has read the Japanese research, because both the cause and cure for the GABAA receptors dispersing and clustering is an increase in calcium and both mediated by glutamate.  

The excitatory neurotransmitter glutamate binds to the mGluR receptor and activates IP3 receptor-dependent calcium release and protein kinase C to promote clustering of GABAA receptors at the postsynaptic membrane - the place on a neuron that receives incoming neurotransmitters from connecting neurons.

If Professor Gargus is correct, and IPR3 does not work properly in autism, the GABAA receptors are likely not sitting there in nice neat clusters. As a result their inhibitory effect is reduced and neurons fire when they should not.

Gargus has found that in the types of autism he has investigated IP3 receptor open as they should, but close too fast and so do not release enough calcium from the cell’s internal calcium store (the endoplasmic reticulum).

In particular the Japanese researchers found that:-

“Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC”
If the IP3 receptor does not stay open as long as it should, not enough Ca2+ will be released and GABA synapses will not be stabilized. Then GABAA receptors will be diffused rather than being in neat clusters.

The science-light version of the Japanese study:-

Just as a thermostat is used to maintain a balanced temperature in a home, different biological processes maintain the balance of almost everything in our bodies, from temperature and oxygen to hormone and blood sugar levels. In our brains, maintaining the balance -- or homeostasis -- between excitation and inhibition within neural circuits is important throughout our lives, and now, researchers at the RIKEN Brain Science Institute and Nagoya University in Japan, and École Normale Supérieure in France have discovered how disturbed inhibitory connections are restored. Published in Cell Reports, the work shows how inhibitory synapses are stabilized when the neurotransmitter glutamate triggers stored calcium to be released from the endoplasmic reticulum in neurons.

"Imbalances in excitation and inhibition in the brain has been linked to several disorders," explains lead author Hiroko Bannai. "In particular, forms of epilepsy and even autism appear to be related to dysfunction in inhibitory connections."

One of the key molecules that regulates excitation/inhibition balance in the brain is the inhibitory neurotransmitter GABA. When GABA binds to GABAA receptors on the outside of a neuron, it prevents that neuron from sending signals to other neurons. The strength of the inhibition can change depending on how these receptors are spaced in the neuron's membrane.

While GABAA receptors are normally clustered together, continual neural activation of NMDA receptors by the neurotransmitter glutamate -- as occurs naturally during learning and memory, or in epilepsy -- leads to an excess of incoming calcium, which ultimately causes the receptors to become more spread out, reducing how much the neuron can be inhibited by GABA.

To combat this effect, the receptors are somehow continually re-clustered, which maintains the proper excitatory/inhibitory balance in the brain. To understand how this is accomplished, the team focused on another signaling pathway that also begins with glutamate, and is known to be important for brain development and the control of neuronal growth.

In this pathway glutamate binds to the mGluR receptor and leads to the release of calcium from internal storage into the neuron's internal environment. Using quantum dot-single particle tracking, the team was able to show that after release, this calcium interacts with protein kinase C to promote clustering of GABAA receptors at the postsynaptic membrane--the place on a neuron that receives incoming neurotransmitters from connecting neurons.

These findings show that glutamate activates distinct receptors and patterns of calcium signaling for opposing control of inhibitory GABA synapses.

Notes Bannai, "it was surprising that the same neurotransmitter that triggers GABAA receptor dispersion from the synapse, also plays a completely opposite role in stabilizing GABAA receptors, and that the processes use different calcium signaling pathways. This shows how complex our bodies are, achieving multiple functions by maximizing a limited number of biological molecules.

Pre-activation of the cluster-forming pathway completely prevented the dispersion of GABAA receptors that normally results from massive excitatory input, as occurs in status epilepticus -- a condition in which epileptic seizures follow one another without recover of consciousness. Bannai explains, "further study of the molecular mechanisms underlying the process we have uncovered could help develop treatments or preventative medication for pathological excitation-inhibition imbalances in the brain.

"The next step in understanding how balance is maintained in the brain is to investigate what controls which pathway is activated by glutamate. Most types of cells use calcium signals to achieve biological functions. On a more basic level, we believe that decoding these signals will help us understand a fundamental biological question: why and how are calcium signals involved in such a variety of biological phenomena?"

The full Japanese study:-

·        Bidirectional synaptic control system by glutamate and Ca2+ signaling

·        Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC

·        Synaptic GABAAR clusters stabilized through regulation of GABAAR lateral diffusion

·        Competition with an NMDAR-dependent Ca2+ pathway driving synaptic destabilization

GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses.

In this study, we demonstrate that the mGluR/IICR/PKC pathway stabilizes GABAergic synapses by constraining lateral diffusion and increasing clustering of GABAARs, without affecting the total number of GABAAR on the cell surface. This pathway defines a unique form of homeostatic regulation of GABAergic transmission under conditions of basal synaptic activity and during recovery from E/I imbalances. The study also highlights the ability of neurons to convert a single neurotransmitter (glutamate) into an asymmetric control system for synaptic efficacy using different calcium-signaling pathways.

The most striking conceptual finding in this study is that two distinct intracellular signaling pathways, NMDAR-driven Ca2+ influx and mGluR-driven Ca2+ release from the ER, effectively driven by the same neurotransmitter, glutamate, have an opposing impact on the stability and function of GABAergic synapses. Sustained Ca2+ influx through ionotropic glutamate receptor-dependent calcium signaling increases GABAAR lateral diffusion, thereby causing the dispersal of synaptic GABAAR, while tonic mGluR-mediated IICR restrains the diffusion of GABAAR, thus increasing its synaptic density. How can Ca2+ influx and IICR exert opposing effects on GABA synaptic structure? Our research indicates that each Ca2+ source activates a different Ca2+-dependent phosphatase/kinase: NMDAR-dependent Ca2+ influx activates calcineurin, while ER Ca2+ release activates PKC.

Taken together, these results lead us to propose the following model for bidirectional competitive regulation of GABAergic synapses by glutamate signaling. Phasic Ca2+ influx through NMDARs following sustained neuronal excitation or injury leads to the activation of calcineurin, overcoming PKC activity and relieving GABAAR diffusion constraints. In contrast, during the maintenance of GABAergic synaptic structures or the recovery from GABAAR dispersal, the ambient tonic mGluR/IICR pathway constrains GABAAR diffusion by PKC activity, overcoming basal calcineurin activity. One possible mechanism of dual regulation of GABAAR by Ca2+ is that each Ca2+-dependent enzyme has a unique sensitivity to the frequency and number of external glutamate release events and can act to decode neuronal inputs (Fujii et al., 2013xNonlinear decoding and asymmetric representation of neuronal input information by CaMKIIα and calcineurin. Fujii, H., Inoue, M., Okuno, H., Sano, Y., Takemoto-Kimura, S., Kitamura, K., Kano, M., and Bito, H. Cell Rep. 2013; 3: 978–987

Abstract | Full Text | Full Text PDF | PubMed | Scopus (24)See all References, Li et al., 2012xCalcium input frequency, duration and amplitude differentially modulate the relative activation of calcineurin and CaMKII. Li, L., Stefan, M.I., and Le Novère, N. PLoS ONE. 2012; 7: e43810

Crossref | PubMed | Scopus (29)See all References, Stefan et al., 2008xAn allosteric model of calmodulin explains differential activation of PP2B and CaMKII. Stefan, M.I., Edelstein, S.J., and Le Novère, N. Proc. Natl. Acad. Sci. USA. 2008; 105: 10768–10773

Crossref | PubMed | Scopus (44)See all References) in inhibitory synapses.

Tight control of E/I balance, the loss of which results in epilepsy and other brain and nervous system diseases/disorders, is dependent on GABAergic synaptic transmission (Mann and Paulsen, 2007xRole of GABAergic inhibition in hippocampal network oscillations. Mann, E.O. and Paulsen, O. Trends Neurosci. 2007; 30: 343–349

Abstract | Full Text | Full Text PDF | PubMed | Scopus (194)See all ReferencesMann and Paulsen, 2007). A recent study showed that the excitation-induced acceleration of GABAAR diffusion and subsequent dispersal of GABAARs from synapses is the cause of generalized epilepsy febrile seizure plus (GEFS+) syndrome (Bouthour et al., 2012xA human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABAA receptors. Bouthour, W., Leroy, F., Emmanuelli, C., Carnaud, M., Dahan, M., Poncer, J.C., and Lévi, S. Cereb. Cortex. 2012; 22: 1542–1553

Crossref | PubMed | Scopus (14)See all ReferencesBouthour et al., 2012). Our results indicate that pre-activation of the mGluR/IICR pathway by DHPG could completely prevent the dispersion of synaptic GABAARs induced by massive excitatory input similar to status epilepticus. Thus, further study of the molecular mechanisms underlying the mGluR/IICR-dependent stabilization of GABAergic synapses via regulation of GABAAR lateral diffusion and synaptic transmission could be helpful in the prevention or treatment of pathological E/I imbalances, for example, in the recovery of GABAergic synapses from epileptic states

DHPG = group I mGluR agonist dihydroxyphenylglycine.

On a practical level you want to inhibit GABAA  dispersion and promote GABAA stabilization. How you might do this would depend on exactly what was the underlying problem.

If the problem is IP3R not releasing enough calcium, you might activate PKC in a different way or just increase the signal from Group 1 mGluR. If the problem is too much calcium influx through NMDA receptors due to excess glutamate, you could increase the re-uptake of glutamate, via GLT-1, using Riluzole.  You could block the flow of Ca2+ through NMDA receptors using an antagonist.

The Japanese used dihydroxyphenylglycine (DHPG) as their Group 1 mGluR agonist.  DHPG is an agonist of mGluR1 and mGluR5.  We have come across mGluR5 many times before in this blog.  Mavoglurant is an experimental drug candidate for the treatment of fragile X syndrome.  It is an antagonist of mGluR5.

We have seen many times before that there is both hypo and hyper function possible and indeed that fragile X is not necessarily a good model for autism.

The selective mGluR5 agonist CHPG protects against traumatic brain injury, which would indeed make sense. Although, that research suggests an entirely different mechanism.

The calcium released by IP3 works in complex way together with DAG (diacylglycerol ) to activate PKC (protein kinase C).

Ideally you would have enough calcium released from IP3, but you could also increase DAG. It depends which part of the process is rate-limiting.

Diacylglycerol (DAG) has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat.  Diglycerides, generally in a mix with monoglycerides are common food additives largely used as emulsifiers. In Europe, when used in food the mix is called E471.


On the one hand things are getting very complicated, but on the other we keep coming back to the same variables (IP3R, mGlur5, GABAA etc.).

It is pretty clear that some very personalized therapy will be needed.  Is it an mGlur5 agonist or antagonist? Or quite possibly neither, because in different parts of the brain it will have a good/bad effect.

It does look like Riluzole should work well in some people.

A safe IP3R agonist looks a possibility. As shown in the diagram earlier in this post,IP3 is usually made in situ, but agonists exist.

In effect autism could be the opposite of Huntington’s disease. In Huntington’s,  type 1 IP3 receptors are  more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in concentrations of Ca2+inside cells and in mitochondria.

According to Gargus we should have reduced concentrations of Ca2+inside cells in autism.

I suspect it is much more complicated in reality, because it is not just the absolute  level of Ca2+ but rather the flow of Ca2+; so it matters where it is coming from. I think we likely have impaired calcium channel activity of multiple types in autism and the actual level of intracellular calcium will not tell you much at all.

As the Japanese commented, it is surprising that glutamate is the neurotransmitter that controls the clustering, or not, of GABAA receptors.  This suggests that you cannot ignore glutamate and just “fix” GABA.