Today’s post
sounds complicated. We actually already know that the gene GABRA5, and hence the
alpha 5 sub-unit of GABAA 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 GABAA
receptors. These combinations are not fixed, or “hard-wired”; they vary all the
time.
The
composition of the GABAA 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.
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 GABAA
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 GABAA signaling,
especially at GABAA α5-subunit containing receptors, might
potentially be a novel therapeutic target for ASD. Unselective GABAA
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 GABAA 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 GABAA α5
expression in adult males with ASD, consistent with the hypothesis that ASD is
characterised by a defect in GABA signaling.
The prevalence of autism
spectrum disorders (ASDs), which affect over 1% of the population, has
increased twofold in recent years. Reduced expression of GABAA
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 GABAA 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 α5GABAA
receptor-anchoring protein radixin, further supporting a α5GABAA
receptor deficiency in ASDs.
The results from
the current study suggest that drugs that act as positive allosteric modulators
of α5GABAA
receptors may ameliorate autism-like behaviors
Too many or too few the α5GABAA
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 α5GABAA, 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 α5GABAA are behaving,
because even if you have an appropriate number of these receptors, you may not
have optimal activity from them. Over activity from α5GABAA 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 α5GABAA. It has been shown that increased α5GABAA 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 (α5GABAA) 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 α5GABAA
receptor function. A tonic inhibitory current generated by α5GABAA
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 α5GABAA
receptors in the hippocampus. Collectively, these results show that α5GABAA 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 GABAA 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 GABAA 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 α5GABAA
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 α5GABAA 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
to use cinnamon/NaB to reduce GABRA5 expression, which
has got to consequently reduce α5GABAA activity.
All of these strategies are crude, because what matters
is α5GABAA 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 α5GABAA 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 α5GABAA 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 α5GABAA 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:-
