Restoring the excitation/inhibition balance in neurons is a good way to treat both epilepsy and autism. Professor Catterall performed the groundwork in one model of epilepsy and one model of autism more than a decade ago, using low-dose clonazepam.
At that point I did endeavour to
translate that science from mouse to human, in part because Professor Catterall
made clear he was not going to.
A number of readers of this blog,
biased towards doctor parents, did use
this therapy for several years.
In 2021 the Chinese showed low-dose
clonazepam effective in the Maternal Immune Activation (MIA) model of autism.
Roll forward to 2025 and Chinese
researchers looking into another single gene autism (SCN2A) have found the same
therapy to be effective. Fancy that !!
It is actually the cheapest therapy I
ever investigated, costing a few dollars/euros/pounds a year.
At a tiny dose, clonazepam, which acts
as a positive allosteric modulator of GABA receptors, enhances the activity of
receptors containing α2 and α3 subunits and restores the excitation/inhibition
balance.
The effective dose in us humans is
about 0.0006 mg/kg per day. Due to its long half-life, you need to take the
dose for 3 days before the level in the body rises to the therapeutic level. As
suggested by Catterall, there is a narrow therapeutic window; too high a dose,
or too low a dose, will not be effective.
I used tablets, but it is much easier
to use the liquid version of clonazepam, since you need to produce a very
dilute version and then measure the dose with a syringe. Some people used a
compounding pharmacy to do the hard work.
Not everyone responds and I think not
everyone finds their therapeutic dosage window. I think people may need to
adjust the dosage over the years.
There are many posts in this blog that
refer to this therapy.
What are the
effects in children?
The effects are improved cognition, ability
to learn new skills and a reduction in broad symptoms of autism.
In kids already taking bumetanide, and are responsive to that therapy, there is an additional benefit. In our case the
incremental effect was less than bumetanide, but welcome nonetheless.
Some people use it as an alternative
to bumetanide, when diuresis is problematic.
The dose is so low, the usual risks of
benzodiazepines are not present. It might be better described as a micro-dose.
The recent paper from 2025:
Social behavior is critical for survival and adaptation, which is profoundly disrupted in autism spectrum disorders (ASD). Social withdrawal due to information overload was often described in ASD, and it was suspected that increased basal noise, i.e., excessive background neuronal activities in the brain could be a disease mechanism. However, experimental test of this hypothesis is limited. Loss-of-function mutations (deficiency) in SCN2A, which encodes the voltage-gated sodium channel NaV1.2, have been revealed as a leading monogenic cause of profound ASD. Here, we revealed that Scn2a deficiency results in robust and multifaceted social impairments in mice. Scn2a-deficient neurons displayed an increased excitation-inhibition (E/I) ratio, contributing to elevated basal neuronal noise and diminished signal-to-noise ratio (SNR) during social interactions. Notably, the restoration of Scn2a expression in adulthood is able to rescue both SNR and social deficits. By balancing the E/I ratio and reducing basal neuronal firing, an FDA-approved GABAA receptor-positive allosteric modulator improves sociability in Scn2a-deficient mice and normalizes neuronal activities in translationally relevant human brain organoids carrying autism-associated SCN2A nonsense mutation. Collectively, our findings revealed a critical role of the NaV1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A-associated disorders.
HIGHLIGHTS
1.
NaV1.2
deficiency leads to pronounced social deficits in mice.
2.
NaV1.2
deficiency results in an overall enhanced E/I ratio, elevated basal neuronal
activity, and impaired signal-to-noise ratio.
3.
Both the enhanced
E/I ratio and impaired sociability are reversible through the restoration of NaV1.2
expression in adulthood.
4.
Targeted
restoration of NaV1.2 in striatum-projecting neurons rescues social
impairments.
5. GABA
transmission is reduced in both mouse and human organoid models of SCN2A deficiency,
and acute systemic administration of GABAA receptor-positive
allosteric modulators restores sociability.
Because
reduced GABAergic signaling can enhance the E/I ratio and contribute to in
vivo neuronal hyperexcitability, we examined whether potentiating GABAA receptor
activity using a positive allosteric modulator (PAM) could normalize neuronal
firing. Notably,
clonazepam, an FDA-approved benzodiazepine has been shown to rescue social
deficits in both a Scn1a knockout model of Dravet syndrome37 and
the BTBR model of idiopathic autism38. In WT mice, baseline recordings from putative
MSNs showed low firing rates that remained unchanged following acute systemic
administration of a low dose of clonazepam (Clz, 0.05 mg/kg, i.p.) (Figure 5C, D). In contrast, clonazepam markedly suppressed the abnormally high firing
rates in HOM mice (Figure 5E, F).
In
summary, our findings reveal that severe NaV1.2 deficiency produces
profound and reversible social deficits, underpinned by disproportionate
reductions in excitatory and inhibitory synaptic transmission. We demonstrate a
direct, dose-dependent relationship between Scn2a expression
and sociability, whereby a ∼70% reduction in NaV1.2 leads to an
elevated E/I ratio, increased noisy basal activity, and impaired neuronal
coding, while restoration of Scn2a or pharmacological
enhancement of GABAA receptor function reverses these deficits.
Collectively, our work provides a comprehensive exploration, from molecular and
cellular mechanisms to neural circuits, of the pathophysiology underlying
social impairments in SCN2A-associated disorders. These insights
lay a robust foundation for the development of targeted therapeutic
interventions aimed at normalizing synaptic function to ameliorate social
impairments.
The original papers from Professor
Catterall in a model of polygenic autism and in Dravet syndrome:
Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T+ Itpr3tf/J (BTBR) mice, a model of idiopathic autism, have reduced spontaneous GABAergic neurotransmission. Treatment with low non-sedating/non-anxiolytic doses of benzodiazepines, which increase inhibitory neurotransmission through positive allosteric modulation of postsynaptic GABAA receptors, improved deficits in social interaction, repetitive behavior, and spatial learning. Moreover, negative allosteric modulation of GABAA receptors impaired social behavior in C57BL/6J and 129SvJ wild-type mice, suggesting reduced inhibitory neurotransmission may contribute to social and cognitive deficits. The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit-specific—the α2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α1-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and α2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.
Autistic
behavior in Scn1a+/− mice and rescue by enhanced
GABAergic transmission
Haploinsufficiency
of the SCN1A gene encoding voltage-gated sodium channel NaV1.1
causes Dravet Syndrome (DS), a childhood neuropsychiatric disorder including
recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors.
The neural mechanisms responsible for cognitive deficit and autism-spectrum
behaviors in DS are poorly understood. Here we show that mice with Scn1a haploinsufficiency
display hyperactivity, stereotyped behaviors, social interaction deficits, and
impaired context-dependent spatial memory. Olfactory sensitivity is retained,
but novel food odors and social odors are aversive to Scn1a+/− mice.
GABAergic neurotransmission is specifically impaired by this mutation, and
selective deletion of NaV1.1 channels in forebrain interneurons is
sufficient to cause these behavioral and cognitive impairments. Remarkably,
treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors,
completely rescued the abnormal social behaviors and deficits in fear memory in
DS mice, demonstrating that they are caused by impaired GABAergic
neurotransmission and not by neuronal damage from recurrent seizures. These
results demonstrate a critical role for NaV1.1 channels in
neuropsychiatric functions and provide a potential therapeutic strategy for
cognitive deficit and autism-spectrum behaviors in DS.
The 2021 paper from China using the
maternal immune activation model of autism:
Ample evidence indicates that maternal immune activation (MIA) during gestation is linked to an increased risk for neurodevelopmental and psychiatric disorders, such as autism spectrum disorder (ASD), anxiety and depression, in offspring. However, the underlying mechanism for such a link remains largely elusive. Here, we performed RNA sequencing (RNA-seq) to examine the transcriptional profiles changes in mice in response to MIA and identified that the expression of Scn1a gene, encoding the pore-forming α-subunit of the brain voltage-gated sodium channel type-1 (NaV1.1) primarily in fast-spiking inhibitory interneurons, was significantly decreased in the medial prefrontal cortex (mPFC) of juvenile offspring after MIA. Moreover, diminished excitatory drive onto interneurons causes reduction of spontaneous gamma-aminobutyric acid (GABA)ergic neurotransmission in the mPFC of MIA offspring, leading to hyperactivity in this brain region. Remarkably, treatment with low-dose benzodiazepines clonazepam, an agonist of GABAA receptors, completely prevented the behavioral abnormalities, including stereotypies, social deficits, anxiety- and depression-like behavior, via increasing inhibitory neurotransmission as well as decreasing neural activity in the mPFC of MIA offspring. Our results demonstrate that decreased expression of NaV1.1 in the mPFC leads to abnormalities in maternal inflammation-related behaviors and provides a potential therapeutic strategy for the abnormal behavioral phenotypes observed in the offspring exposed to MIA.
Conclusion
On the one
hand, it is great that you can use this published research to treat your own child, but
it is rather sad that this research is never going to be applied widely to
children with severe autism.
Professor
Catterall did not want to take on the massive task of “commercializing” his
discovery. It would be a huge and expensive job, with no financial return, since
clonazepam is already a widely available cheap generic drug.
This is the
same problem faced by bumetanide, leucovorin and other generic drugs that can be
repurposed for autism.
You have to
adjust to the imperfect world we live in, rather than assume everything is
being done on your child’s behalf, by those thousands of autism researchers.
They want to get published and get paid — that is their success. For me, what matters is getting results, and I did. Hopefully, so will you.
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