Variable Expression of GABRA5 and Activation of α5 - a Modifier of Cognitive Function in Autism?

Today’s post sounds complicated. We actually already know that the gene GABRA5, and hence the alpha 5 sub-unit of GABA_A receptors, can affect cognition, but we do not know for sure in whom it is relevant.

Most readers of this blog are lay people, as such we tend to be predisposed to the idea that autism is somehow “hardwired”, something that just happened and cannot be reversed. Some of autism is indeed “hardwired”, you cannot take an adult with autism and “re-prune” his synapses, to produce a more elegant robust network in his brain. But much can be done, because many things in the brain are changing all the time, they are not fixed at all. Today’s post is good example.

GABA is the most important inhibitory neurotransmitter in the brain. There are two types of GABA receptor, A and B. These receptors are made up of sub-units. There are many different possible combinations of sub-units to make GABA_A receptors. These combinations are not fixed, or “hard-wired”; they vary all the time.

The composition of the GABA_A receptor changes its effect. It can change how you feel (anxiety) and it can change you think/learn.

You can actually measure GABRA5 expression in different regions of the brain in a test subject using a PET-CT (Positron Emission Tomography–Computed Tomography) scan and it has been done in some adults with high functioning autism. This machine looks like a big front-leading washing machine, just a bit cleverer. 

The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study

our primary hypothesis was that, compared to controls, individuals with ASD have a significant reduction in α5 GABA receptor availability in these areas.

Due to the small sample size, we could not examine possible correlations between GABA_A binding and particular symptoms of ASD, age, IQ, or symptoms of comorbidities frequently associated with ASD, such as anxiety disorders, OCD and depression. We were also unable to address the effects of possible neuroanatomical differences between people with ASD and controls, which might lead to partial volume effects in PET studies. However, the modest magnitude of the volumetric differences seen in most studies of high-functioning ASD suggests that it is unlikely that these could fully explain the present findings.

These preliminary results suggest that potentiation of GABA_A signaling, especially at GABA_A α5-subunit containing receptors, might potentially be a novel therapeutic target for ASD. Unselective GABA_A agonists and positive allosteric modulators, such as benzodiazepines, have undesirable features such as abuse potential and tolerance, but more selective modulators might avoid such limitations. Further research should extend this work in a larger sample of ASD individuals. It would also be interesting to use PET with the ligand [¹¹C]Ro15-4513 to measure GABA_A in disorders of known etiology characterised by ASD symptoms, such as Fragile X and 15q11-13 duplication

In summary, we present preliminary evidence of reduced GABA_A α5 expression in adult males with ASD, consistent with the hypothesis that ASD is characterised by a defect in GABA signaling. 

α5GABAA receptor deficiency causes autism-like behaviors

The prevalence of autism spectrum disorders (ASDs), which affect over 1% of the population, has increased twofold in recent years. Reduced expression of GABA_A receptors has been observed in postmortem brain tissue and neuroimaging of individuals with ASDs. We found that deletion of the gene for the α5 subunit of the GABA_A receptor caused robust autism-like behaviors in mice, including reduced social contacts and vocalizations. Screening of human exome sequencing data from 396 ASD subjects revealed potential missense mutations in GABRA5 and in RDX, the gene for the α5GABA_A receptor-anchoring protein radixin, further supporting a α5GABA_A receptor deficiency in ASDs.

The results from the current study suggest that drugs that act as positive allosteric modulators of α5GABA_A receptors may ameliorate autism-like behaviors 

  

Too many or too few the α5GABA_A receptors or too much/little activity?

Regular readers will know that autism is all about extremes hypo/hyper, macro/micro etc. The same is true with α5GABA_A, too few can cause autistic behaviors, but too many can impede learning. You need just the right amount.

The next variable is how well your α5GABA_A are behaving, because even if you have an appropriate number of these receptors, you may not have optimal activity from them. Over activity from α5GABA_A is likely to have the same effect as having too many of them.

Here it becomes very relevant to many with autism and inflammatory comorbidities, because systemic inflammation has been shown to activate α5GABA_A. It has been shown that increased α5GABA_A receptor activity contributes to inflammation-induced memory deficits and, by my extension, to inflammation-induced cognitive decline.

α5GABAA Receptors Regulate Inflammation-Induced Impairment of Long-Term Potentiation

Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABA_A) receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABA_A receptor function. A tonic inhibitory current generated by α5GABA_A receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABA_A receptors in the hippocampus. Collectively, these results show that α5GABA_A receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

We saw in an earlier post that overexpression of GABRA5 is found in slow learners and we know that this is a key target of Down Syndrome research, aimed at raising cognitive function.

What can be modified?

It appears that you can modify the expression of GABRA5, which means you can increase/decrease the number of GABA_A receptors that contain an α5 subunit.

You can also tune the response of those α5 subunits. You can increase it or decrease it.

Activation of the α₅ subunit is thought to be the reason why benzodiazepine drugs  have cognitive (reducing) side effects. By extension, inverse agonists of α₅ are seen as likely to be nootropic.

One such drug is LS-193,268  is a nootropic drug invented in 2004 by a team working for Merck, Sharp and Dohme.

A complication is that you do not want to affect the α₂ subunit, or you will cause anxiety. So you need a highly selective inverse agonist.

The new Down Syndrome drug, Basmisanil, is just such a selective inverse agonist of α₅.

“Basmisanil (developmental code names RG-1662, RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α₅ subunit-containing GABA_A receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome.  As of August 2015, it is in phase II clinical trials for this indication.^“

A contradiction

As is often the case, there is an apparent contradiction, because on the one hand a negative allosteric modulator should be nootropic in NT people and appears to raise cognition in models of Down Syndrome; but on the other hand results from a recent study suggests that drugs that act as positive allosteric modulators of α5GABA_A receptors may ameliorate autism-like behaviors.

So which is it?

Quite likely both are right.

It is exactly as we saw a long while back with NMDAR activity, some people have too much and some have too little. Some respond to an agonist, some to an antagonist and some to neither.

What we can say is that fine-tuning α5GABA_A in man and mouse seems a viable option to enhance cognition in those with learning difficulties.

The clever option is probably the positive/negative allosteric modulator route, the one being pursued by big Pharma for Down Syndrome.

I like Dr Pahan’s strategy from this previous post, for poor learners and those with early dementia

https://epiphanyasd.blogspot.com/2017/10/sodium-benzoate-and-gabra5.html

to use cinnamon/NaB to reduce GABRA5 expression, which has got to consequently reduce α5GABA_A activity.

All of these strategies are crude, because what matters is α5GABA_A activity in each part of the brain. This is why changing GABRA5 expression will inevitably have good effects in one area and negative effects in another area. What matter is the net effect, is it good, bad or negligible?

The fact that systemic inflammation increases α5GABA_A activity may contribute to the cognitive decline some people with autism experience.

We previously saw how inflammation changes KCC2 expression and hence potentially increases intra cellular chloride, shifting GABA towards excitatory.

Ideally you would avoid systemic inflammation, but in fact all you can do is treat it.

Increasing α5GABA_A activity I would see as possible strategy for people with high IQ, but some autistic features.

I think those with learning problems are likely to be the ones wanting less α5GABA_A activity.

The people for whom “bumetanide has stopped working” or “NAC has stopped working” are perhaps the ones who have developed systemic inflammation for some reason.  You might only have to measure C-reactive protein (CRP) to prove this.

More reading for those interested:-

The α-5 subunit-containing GABA-A receptor: a target for the treatment of cognitive defects

The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia

Cognitive Impairment in Schizophrenia, Bipolar & Autism

Neurological/neuropsychiatric disorders are often poorly described and poorly treated, but adult-onset conditions have historically been taken much more seriously and so the research is more advanced .  I find myself quite often looking at research on schizophrenia and bipolar; many of the same genes and metabolic dysfunctions common in autism show up in those conditions.

Many people really dislike the term Mental Retardation (MR), which is actually a very accurate descriptive term, meaning that someone is cognitively behind their peers.  Most lay people have no idea what Intellectual Disability (ID) means.

It is interesting that about 90% of people with schizophrenia and 50% of people with bipolar are cognitively behind their peers.  I suspect the figure for autism would also be about 90%, if someone measured it.  Most people with Asperger’s are not top of the class.

Only in extreme cases of being cognitively behind their peers, when their IQ is less than 70, does a person get diagnosed with MR/ID.

So the clinical diagnosis of MR/ID is just an arbitrary cut-off point.  The idea that if IQ is greater than 70 there is no cognitive deficit is entirely flawed.

It seems than in autism, as in schizophrenia and bipolar we should assume that cognitive dysfunction is present; the only question is how much and what to do about it.

Having treated the cognitive dysfunction(s), the person is then in a better place to compensate for the other dysfunctions they might have.

Even though the psychiatrists and psychologists will tell you that autism is all about the triad of impairments, I think they are missing the most important element, which is cognitive dysfunction.

As people with autism age, many find their symptoms associated with the above “triad of impairments” mellow.  The substantial minority who experience untreated flare-ups driven by inflammation caused by things like allergy, GI problems and even juvenile arthritis may not be so lucky.

I imagine that cognitive function in adulthood remains at the level it reached as a teenager.

Cognitive Function as the Therapeutic Target

Since many children with autism do eventually overcome many of their challenges in childhood, perhaps cognitive function really should be given a higher priority in treatment and research.

Many caregivers and educators are mainly focused on minimizing bad/disruptive behaviors (and bruises) rather than the emergence of good behaviors and learning.  This is sad but true.

As the child matures, in many cases these bad/disruptive behaviors may fade without any clever interventions.

So an intervention that stops stereotypy in a toddler, which was blocking learning, may have very much less impact in an adolescent.  Or at least the impact may be much less obvious.

I remember reading about a parent with two children with Fragile-X who was very upset when the Arbaclofen trials were halted, since her kids had responded well.  But two years later in another article it was clear that things were going fine without Arbaclofen.  The son whose violence towards his mother had been controlled by Arbaclofen, was no longer aggressive.  He continued to suffer cognitively, being a male with Fragile-X, the sister was much less affected  (females with fragile X syndrome have two X chromosomes and only one of the chromosomes usually have an abnormal gene, so usually females are less affected).   

The advantage of using cognitive function as a target is that it is much easier to measure than subjective behavioral deficits.  For the majority of people it is likely to be the most important factor in their future success and well-being.

In the substantial minority of cases where there are seizures and/or factors causing autism flare-ups, the behavioral deficits may remain undiminished into adulthood.  These people would also benefit from maximized cognitive function.

Cognitive Deficit in Schizophrenia & Bipolar (BPD)

To most lay people schizophrenia is characterized by abnormal social behavior and failure to recognize what is real. Common symptoms include false beliefs, unclear or confused thinking, hearing voices, reduced social engagement and emotional expression, and a lack of motivation. People often have additional mental health problems such as major depression, anxiety disorders, or substance use disorder. Symptoms typically come on gradually, begin in early adulthood, and last a long time.

Cognitive impairments and psychopathological parameters in patients of the schizophrenic spectrum.

  

Abstract

Cognitive impairment is a core feature of schizophrenia and it is considered by many researchers as one of the dimensional components of the disorder. Cognitive dysfunction occurs in 85% of schizophrenic patients and it is negatively associated with the outcome of the disorder, the psychosocial functioning of the patients, and non-compliance with treatment. Many different cognitive domains are impaired in schizophrenia, such as attention, memory, executive functions and speech. Nowadays, it is argued that apart from clinical heterogeneity of schizophrenia, there is probable heterogeneity in the accompanying neurocognitive dysfunction. Recent studies for cognitive dysfunction in schizophrenia employ computerized assessment batteries of cognitive tests, designed to assess specific cognitive impairments. Computerized cognitive testing permits for more detailed data collection (e.g. precise timing scores of responses), eliminates researcher's measurement errors and bias, assists the manipulation of data collected, and improves reliability of measurements through standardized data collection methods. The aims of the present study are: the comparison of cognitive performance of our sample of patients and that of healthy controls, on different specific cognitive tests, and the testing for possible association between patients' psychopathological symptoms and specific cognitive impairments, using the Cogtest computerized cognitive assessment battery. 71 male inpatients diagnosed with schizophrenia or other psychotic spectrum disorders (mean = 30.23 ± 7.71 years of age), admitted in a psychiatric unit of the First Department of Psychiatry, Athens University Medical School, Eginition Hospital (continuous admissions) were studied. Patients were excluded from the study if they suffered from severe neurological conditions, severe visual or hearing impairment, mental retardation, or if they abused alcohol or drugs.

Bipolar disorder, also known as bipolar affective disorder or manic depression, is a mental disorder characterized by periods of depression and periods of elevated mood. The elevated mood is significant and is known as mania or hypomania depending on the severity or whether symptoms of psychosis are present. During mania an individual feels or acts abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life

It also turns out that cognitive deficit is generally present in bipolar disorder (BPD).

Understanding Cognitive Impairments in Bipolar Disorder and Psychosis

  

“One area that Dr. Burdick is exploring is the frequency of neurocognitive impairment in BPD. Research shows that approximately 90 percent of schizophrenic patients suffer from cognitive deficits compared to only 40 to 60 percent of BPD patients. Understanding why certain patients develop significant cognitive difficulties while others do not is critical in optimizing patients’ quality of life, she says.”

Bipolar is probably not something you would connect with autism.  Being an observational diagnosis you would not tend to look at the biological underpinnings. The biological basis of both bipolar and schizophrenia are far better studied than autism and do significantly overlap with it.

In a recent post I looked at epigenetics and autism, when it comes to schizophrenia and bipolar the role of epigenetics is far more in the mainstream.

There is an approved epigenetic therapy (the HDAC inhibitor Valproate) for Bipolar mania and there is a clinical trial to improve cognitive function in schizophrenia using ather epigenetic therapy (the HDAC inhibitor Sodium Butyrate.)

Butyrate is also showed promise in a mouse model (D-AMPH) of Bipolar.

Sodium Butyrate For Improving Cognitive Function In Schizophrenia

Epigenetic mechanisms in schizophrenia

Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of D-AMPH

Conclusion

I think people should be more open to discuss cognitive deficits and not hide behind politically correct terminology.

It seems that in both bipolar and schizophrenia cognitive deficits are recognized to be at the core of the disorder, even though 99% will not have an IQ<70 and so not be labelled with MR/ID.

Autism therapies which clearly improve cognitive function, like Bumetanide and low-dose Clonazepam, should be promoted as such.  Clinical trials should measure the cognitive improvement separately from autism measures.  As the person ages I think the benefit will often be more noticeable/measurable cognitively than behaviorally.