Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

 

  

 

There are at least 2 Natasas I can think of who will like this post.

Today’s post revisits the subject of calcium channels in autism.  Ion channel dysfunctions are a favourite area of mine because many should be treatable by repurposing safe, existing drugs. I do take note that many readers of this blog have reported success by targeting L-type calcium channels.

Many years ago, at the start of this blog, I recall reading about Timothy syndrome and a researcher at Stanford, Ricardo Dolmetsch, who was exploring treatment using a T-type calcium channel blocker.  It turned out that he had a son with severe autism, which was driving his interest at that time. He won all kinds of awards, but I always wondered why he did not treat his own son.

It is quite strange because Timothy syndrome is caused by a gain of function of an L-type channel. This mutation causes the Cav1.2 channel to fail to inactivate properly after opening. As a result, there is prolonged calcium influx into cells.

Instead of blocking Cav1.2, the researchers blocked the T-channels Cav3.2 and 3.3.

I did my homework on idiopathic autism a dozen years ago and concluded I needed to block Cav1.2. I went ahead and did it – it works like a charm.

It was a real drama back in those days, with self-injury and aggression, so Timothy syndrome and T channels remains stuck in my mind a decade later.

 

Language Genes

Even before parents worry about self-injurious behavior (SIB), they go through the phase of worrying about if their child will ever speak. Some do and some do not.  What really matters is communication, rather than speech.

 

FOXP2 - The language Gene

FOXP2 is a transcription factor involved in the development of neural circuits related to speech and language production, particularly in areas such as the basal ganglia and cerebellum. Mutations in FOXP2 can lead to speech and language deficits.

FOXP2 influences motor control and vocalization processes that are critical for speech, and it is thought to have evolved specifically in humans to support complex language abilities.

 

CNTNAP2 - The language-associated gene

CNTNAP2 (Contactin-associated protein-like 2) is a gene that encodes a cell adhesion protein. It plays a critical role in the development of neural connectivity and the formation of synapses in areas of the brain involved in language, such as the broca’s area and temporal lobes. CNTNAP2 is also involved in the regulation of neuronal excitability and is crucial for the development of white matter tracts that connect language-related brain regions.

Mutations in CNTNAP2 have been implicated in neurodevelopmental disorders such as specific language impairment (SLI), autism, and developmental language disorders.

 

FOXP2 and CNTNAP2 Interaction

FOXP2 and CNTNAP2 work together in the development of the neural circuits that are crucial for language and speech. They are both involved in the formation and maintenance of synaptic connections in key brain regions like the cortex, basal ganglia, and cerebellum, which are critical for motor control, vocalization, and language processing.

There is evidence to suggest that FOXP2 may regulate the expression of CNTNAP2 as part of a broader gene network that governs language development. FOXP2 may influence CNTNAP2 gene expression, which in turn impacts neural connectivity and synaptic function in brain regions responsible for speech and language.

 

CNTNAP2 sounds familiar?

We have come across this gene before.

At least one reader has a child with a mutation in this gene.

We also discovered that the Pitt Hopkins gene TCF4 regulates CNTNAP2 and that

“PTHS (Pitt Hopkins syndrome) is characterised by severe intellectual disability, absent or severely impaired speech, characteristic facial features and epilepsy. Many of these features are shared with patients carrying CNTNAP2 mutations, leading researchers to test patients with PTHS-like features for CNTNAP2 mutations”

Several readers have children with PTHS (Pitt Hopkins syndrome).

It is not inconceivable that what works for CNTNAP2 will also work for at least some PTHS (Pitt Hopkins syndrome).

The question is whether what works for CNTNAP2 will work much more broadly and could it even improve language development?

Here is the recent research from Stanford:

 

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Dysregulation of thalamocortical circuits has been implicated in these comorbid features, yet their precise roles in ASD pathophysiology remain elusive. This study focuses on the reticular thalamic nucleus (RT), a key regulator of thalamocortical interactions, to elucidate its contribution to ASD-related behavioral deficits using a Cntnap2 knockout (KO) mouse model. Our behavioral and EEG analyses comparing Cntnap2^+/+ and Cntnap2^-/- mice demonstrated that Cntnap2 knockout heightened seizure susceptibility, elevated locomotor activity, and produced hallmark ASD phenotypes, including social deficits, and repetitive behaviors. Electrophysiological recordings from thalamic brain slices revealed increased spontaneous and evoked network oscillations with increased RT excitability due to enhanced T-type calcium currents and burst firing. We observed behavior related heightened RT population activity in vivo with fiber photometry. Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD.

Teaser RT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction.

 

Overall, this study identifies elevated RT burst firing and aberrant thalamic oscillatory dynamics in Cntnap2^−/− mice as a key driver of ASD-related behavioral deficits. If this is a common mechanism of ASD-circuit pathology arising from a variety of genetic causes, then compounds such as Z944, or subtype specific T-type calcium channel antagonists that would target the Cav3.2 and Cav3.3 expressed in RT neurons, might be an effective therapeutic strategy. Furthermore, future research should focus on elucidating RT’s roles in sensory, emotional, and sleep regulation to optimize therapeutic strategies in the context of ASD.

 

Existing T-type calcium channel blockers for humans

Mibefradil is one of the most well-known T-type calcium channel blockers. It was initially developed for hypertension and angina because of its ability to block T-type channels. However, mibefradil was withdrawn from the market in 1998 due to serious drug interactions with other medications, particularly those that inhibit liver enzymes involved in drug metabolism, like statins.

Despite its withdrawal, mibefradil has been studied for other potential uses, including in epilepsy and chronic pain, due to its effects on neuronal excitability.

Zonisamide is an anticonvulsant medication that has some T-type calcium channel blocking properties. It is approved for epilepsy and partial seizures, but it is not typically used specifically for Timothy syndrome or conditions involving T-type channel dysfunction.

Zonisamide is also used to treat seizures in pet dogs and cats.  

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Zonisamide is a novel antiepileptic drug (AED) that was developed in search of a less toxic, more effective anticonvulsant. The drug has been used in Japan since 1989, and is effective for simple and complex partial seizures, generalized tonic-clonic seizures, myoclonic epilepsies, Lennox–Gastaut syndrome, and infantile spasms. In Japan, zonisamide is currently indicated for monotherapy and adjunctive therapy for partial onset and generalized onset seizures in adults and children. In the United States, zonisamide was approved by the Food and Drug Administration (FDA) in 2000 as an adjunctive treatment for partial seizures.

The drug’s broad spectrum of activity and favorable pharmacokinetic profile offer certain advantages in the epilepsy treatment armamentarium. Chemically distinct from other AEDs, zonisamide has been shown to be effective in patients whose seizures are resistant to other AEDs. Zonisamide’s long plasma elimination half-life has allowed it to be used in a once-daily or twice-daily treatment regimen in Japan.

It is believed that zonisamide’s effect on the propagation of seizure discharges involves blocking the repetitive firing of voltage-sensitive sodium channels, and reducing voltage-sensitive T-type calcium currents without affecting L-type calcium currents. These mechanisms stabilize neuronal membranes and suppress neuronal hypersynchronization, leading to the suppression of partial seizures and generalized tonic–clonic seizures in humans.

Zonisamide possesses mechanisms of action that are similar to those of sodium valproate, e.g., suppression of epileptogenic activity and depression of neuronal responses. These mechanisms are thought to contribute to the suppression of absence and myoclonic seizures.

  

Conclusion

It would seem that zonisamide should be trialed in:

·        CNTNAP2-related neurodevelopmental disorder

·        Pitt Hopkins syndrome (PTHS)

·        Timothy syndrome

·        Idiopathic/polygenic autism

(But, don’t hold your breath!)

Due to the nature of CNTNAP2 disorder and PTHS, I think the greatest impact will be if given from a very young age. However, we do see improvements with many autism interventions regardless of age.

It is certainly conceivable that even mild autism can benefit from damping down reticular thalamic (RT) hyperexcitability.

If shown effective, zonisamide would join the long list of anti-epileptic drugs (AEDs) “repurposable” to treat certain subtypes of autism.