Excitatory/Inhibitory (E/I) imbalances as a unifying, treatable, feature of severe autism that cause Cognitive Impairment, Self-Injurious Behavior (SIB) and ultimately seizures in some

 

Autism is a complex condition that manifests in a range of symptoms, from social and communication challenges to sensory sensitivities and repetitive behaviors. Researchers long ago identified a key neurobiological mechanism that underlies many of the core and associated features of autism: excitatory/inhibitory (E/I) imbalances in the brain.

These imbalances, where the delicate interplay between neuronal excitation and inhibition is disrupted, offers a unifying framework to explain certain severe manifestations of autism, including cognitive impairment, self-injurious behavior (SIB), and seizures. Understanding E/I imbalance not only sheds light on the biology of autism but also opens new avenues for targeted therapies.

 

The Role of E/I Balance in the Brain

Neuronal circuits rely on a finely tuned balance between excitatory and inhibitory signals to function properly. Excitatory neurons promote the firing of signals, enabling processes like learning, memory, and sensory integration. Inhibitory neurons, on the other hand, dampen excessive activity, ensuring stability and preventing overstimulation.

In individuals with autism, this balance is often disrupted. Overactive excitatory signaling or insufficient inhibitory control can lead to hyperexcitability in certain brain regions, contributing to behavioral and neurological symptoms. This imbalance is influenced by a range of factors, including:

• Genetic mutations in key synaptic proteins (e.g., SHANK3, SCN1A, GABA receptor subunits).
• Neuroinflammation and oxidative stress.
• Developmental disruptions in synaptic pruning or circuit formation.

 

How E/I imbalances drives severe autism symptoms

 

Cognitive Impairment

E/I imbalance affects the prefrontal cortex and hippocampus, regions critical for cognitive functions like problem-solving, memory, and attention. Disrupted neural signaling in these areas impairs synaptic plasticity—the brain’s ability to adapt and learn—which can manifest as intellectual disability in some individuals with autism.

Studies have shown that restoring E/I balance in animal models can improve cognitive deficits, highlighting its central role in intellectual development.

 

Self-Injurious Behavior (SIB)

Self-injurious behaviors, such as head-banging or skin-picking, are often linked to dysregulated sensory processing and impaired impulse control. Hyperexcitability in brain regions like the amygdala can heighten stress responses, while altered pain thresholds caused by E/I imbalance may make some individuals less sensitive to injury.

Addressing the underlying imbalance can reduce the neural hyperactivity driving these behaviors and improve emotional regulation.

 

Seizures

Seizures are a common comorbidity in autism, affecting up to 30% of individuals. They arise directly from hyperexcitability in neural networks, where excessive excitation leads to abnormal, synchronized firing of neurons. Genetic conditions like Dravet syndrome, linked to mutations in sodium channel genes (e.g., SCN1A), exemplify the connection between E/I imbalance and epilepsy.

Therapies that stabilize E/I balance, such as GABA-enhancing drugs or ion channel modulators, have shown promise in reducing seizure frequency and severity.

 

Targeting E/I Imbalance: A Path Toward Better Treatments

Given its central role in severe autism symptoms, E/I imbalance represents a promising target for therapeutic intervention. Approaches to restore balance include:

 

Pharmacological Therapies

Bumetanide

Bumetanide is a diuretic that also affects neuronal chloride homeostasis by inhibiting the NKCC1 transporter. In autism, elevated intracellular chloride levels impair the function of GABA, shifting its action from inhibitory to excitatory. Bumetanide lowers intracellular chloride, restoring GABA’s inhibitory effect and reducing hyperexcitability. Clinical trials have shown improvements in social behaviors and reduced severity of core autism symptoms in some individuals.

 

L-Type Calcium Channel Blockers

L-type calcium channels play a role in synaptic plasticity and neuronal excitability. Excessive calcium influx can contribute to hyperexcitability and oxidative stress. Blockers like nimodipine and verapamil may help stabilize neuronal activity and have shown potential in reducing seizures and hyperactivity in preclinical studies.

 

T-Type Calcium Channel Blockers

T-type calcium channels are involved in regulating burst firing and thalamocortical oscillations. Dysregulation of these channels can contribute to sensory processing abnormalities and seizures. Agents like zonisade, traditionally used for absence seizures, may also offer benefits in addressing E/I imbalances in autism.

 

Memantine

Memantine is an NMDA receptor antagonist that modulates glutamatergic signaling. By dampening excessive excitatory activity, it can reduce hyperexcitability and improve cognitive and behavioral symptoms. Clinical studies have shown mixed results, with some individuals experiencing notable benefits in areas like communication and social interactions.

 

Low-Dose Clonazepam

Clonazepam, a benzodiazepine, enhances GABAergic inhibition by increasing the activity of GABA-A receptors. At low doses, it can stabilize neural circuits without causing significant sedation. It has been used off-label to manage anxiety, hyperactivity, and seizures in autism.

 

Valproate

Valproate is an anticonvulsant and mood stabilizer that enhances GABAergic signaling and reduces excessive excitation. It has shown efficacy in managing seizures and may also improve irritability and aggression in some individuals with autism.

 

Baclofen and R-Baclofen

Baclofen is a GABA-B receptor agonist that enhances inhibitory signaling. It can modulate overactive NMDA receptor activity, which may be beneficial in cases of excitatory dysfunction. Baclofen has been studied for its role in reducing repetitive behaviors and improving social interaction in preclinical models.

 

Taurine

Taurine is an amino acid with inhibitory properties that can enhance GABAergic activity and reduce excitatory signaling. It also acts as an antioxidant, mitigating oxidative stress linked to hyperexcitability.

 

Pioglitazone

Pioglitazone, a PPAR-gamma agonist, has anti-inflammatory effects that can indirectly stabilize neural circuits by reducing neuroinflammation associated with E/I imbalances. Preliminary studies suggest it may have benefits for behavioral symptoms in autism.

Other agents including

• Anti-inflammatory Drugs: Minocycline and mefenamic acid reduce neuroinflammation, which can exacerbate E/I imbalances.
• Ion Channel Modulators: Sodium channel blockers like lamotrigine and carbamazepine stabilize hyperexcitable neurons and may reduce both seizures and behavioral dysregulation.

 

Neuromodulation Techniques

• Transcranial Magnetic Stimulation (TMS): A non-invasive method to modulate cortical excitability.
• Transcranial Direct Current Stimulation (tDCS): Targets specific brain regions to enhance or suppress neural activity.

 

 

The Role of NMDA and GABA Receptors in E/I Imbalance

Excitatory NMDA receptors and inhibitory GABA receptors play central roles in maintaining E/I balance. NMDA receptor dysfunction, characterized by either hyperactivity or hypoactivity, is implicated in autism. Overactive NMDA receptors can amplify excitatory signaling, while underactive NMDA receptors can impair synaptic plasticity. Both scenarios disrupt neural communication and contribute to autism-related symptoms.

GABA receptors, particularly GABA-A and GABA-B subtypes, are essential for inhibitory control. Dysfunctional GABAergic signaling reduces the brain’s ability to counterbalance excitation, leading to hyperexcitability.

Baclofen’s modulation of GABA-B receptors exemplifies how targeting these systems can restore balance. By reducing NMDA receptor overactivation and enhancing GABAergic inhibition, baclofen addresses multiple aspects of E/I dysregulation.

 

NMDA receptor dysfunction

Addressing NMDA receptor dysfunction requires a nuanced approach because the receptor can be either hypoactive/underactive or hyperactive/overactive in autism, depending on the individual and the specific neural circuits involved. Treatments vary based on the direction of dysfunction:

 

Treating NMDA Hypofunction

In cases where NMDA receptors are underactive, excitatory signaling is insufficient, leading to impairments in synaptic plasticity, learning, and memory. Strategies to enhance NMDA receptor activity include:

1. D-Cycloserine
• Acts as a partial agonist at the glycine site of the NMDA receptor.
• Enhances receptor activity without overactivation, making it useful for improving social and cognitive functions in some individuals with autism.
2. Sarcosine
• A glycine transport inhibitor that increases synaptic glycine levels, promoting NMDA receptor activation.
• Preclinical studies suggest potential improvements in behavioral symptoms.
3. Glycine Supplements
• Directly increase the availability of a co-agonist required for NMDA receptor activation.
• May improve signaling in circuits where glycine levels are suboptimal.

 

Treating NMDA Hyperfunction

Excessive NMDA receptor activity can lead to excitotoxicity.  When there is too much glutamate or an overactive NMDA receptor, the influx of calcium ions into the neuron becomes excessive. This causes a series of harmful processes contributing to neuronal damage, increased oxidative stress, and seizures. Strategies to dampen NMDA receptor overactivity include:

1. Memantine
• An NMDA receptor antagonist that reduces overactivation without completely shutting down receptor function.
• Clinical trials in autism have reported mixed results but some individuals benefit in areas like hyperactivity and irritability.
2. Magnesium Supplements
• Magnesium acts as a natural blocker of the NMDA receptor under resting conditions.
• Supplementation can stabilize receptor activity and reduce hyperexcitability.
3. Low-Dose Ketamine
• At sub-anesthetic doses, ketamine modulates NMDA receptor activity and enhances synaptic plasticity.
• Emerging research suggests potential benefits for specific autism symptoms, although risks and side effects must be carefully managed.
4. Antioxidants (e.g., N-Acetylcysteine, Vitamin E)
• Reduce oxidative stress caused by NMDA receptor hyperactivity.
• Support neuronal health and may mitigate excitotoxicity.

 

Balancing NMDA Dysfunction

In some cases, the same individual may show hypoactivity in some circuits and hyperactivity in others.

Combining treatments tailored to the specific functional state of NMDA receptors in different brain regions. For example, Low-dose ketamine or memantine may help dampen excessive NMDA activity in the amygdala or basal ganglia, while D-cycloserine might be used to enhance NMDA function in areas like the prefrontal cortex.

  

Calcium, Sodium and Potassium Channels

Calcium signaling is critical for excitatory neurotransmission, as calcium ions mediate glutamate release and synaptic plasticity. Dysregulated calcium channels, such as overactive L-type or T-type channels, contribute to hyperexcitability and sensory abnormalities.

Sodium channelopathies, involving mutations in genes like SCN1A, directly impact neuronal firing rates. Excessive sodium influx leads to hyperactive neurons, causing seizures and other excitatory-driven symptoms. While calcium channels influence neurotransmitter release, sodium channel dysfunction primarily affects action potential generation.

Potassium channels, responsible for repolarizing neurons after firing, also play a key role in maintaining neural stability. Mutations in potassium channel genes can prolong neuronal firing and contribute to hyperexcitability.

 

Conclusion

While E/I imbalance is not the sole cause of autism, it is a key unifying feature that connects many severe symptoms. By targeting this imbalance, clinicians can develop more precise and effective treatments tailored to the individual’s needs. Early intervention, particularly during critical periods of brain development, holds the greatest potential for improving outcomes.

As we continue to unravel the complexities of autism, the concept of E/I imbalance serves as a key nexus to understand, and more importantly, treat the challenges faced by individuals with severe autism and their families. By restoring balance, to the extent possible, both in the brain and in daily life, we can empower those with severe autism to reach their full potential. 

People with mild autism are likely affected by less extreme E/I imbalances, but they may be more aware of them. They are likely easier to treat. The principles are the same. 

The issue of sound sensitivity can affect autism from level 0 (including self-diagnosed and ADHD) all the way to level 3; it is complex because it involves both an E/I imbalance and further issues. There will be a summary post on this subject. 

 

Low-dose clonazepam for autism - SCN2A deficient, SCN1A deficient, BTBR polygenic autism and Maternal Immune Activation (MIA) all respond to the same cheap treatment

 

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.

 

https://www.epiphanyasd.com/search/label/Clonazepam

 

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 science, for those who are interested:

 

The recent paper from 2025:

  

Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associated Scn2a-deficiency

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 Na_V1.2, 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 GABA_A 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 Na_V1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A-associated disorders.

HIGHLIGHTS

1.     Na_V1.2 deficiency leads to pronounced social deficits in mice.

2.     Na_V1.2 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 Na_V1.2 expression in adulthood.

4.     Targeted restoration of Na_V1.2 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 GABA_A 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 GABA_A 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 Na_V1.2 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 Na_V1.2 leads to an elevated E/I ratio, increased noisy basal activity, and impaired neuronal coding, while restoration of Scn2a or pharmacological enhancement of GABA_A 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:

 

Enhancement of Inhibitory Neurotransmission by GABA_A Receptors Having α_2,3-Subunits Ameliorates Behavioral Deficits in a Mouse Model of Autism

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⁺ Itpr3^tf/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 GABA_A receptors, improved deficits in social interaction, repetitive behavior, and spatial learning. Moreover, negative allosteric modulation of GABA_A 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 α_2,3-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 α_2,3-subunit-selective positive GABA_A 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 Na_V1.1 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 Na_V1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA_A 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 Na_V1.1 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:

  

Clonazepam attenuates neurobehavioral abnormalities in offspring exposed to maternal immune activation by enhancing GABAergic neurotransmission

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 (Na_V1.1) 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 GABA_A 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 Na_V1.1 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.