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:
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.
Peter, I might have missed this in earlier blogs. Did you know Bumetanide decreases Nitric Oxide?
ReplyDeleteSodium channels are required during in vivo sodium chloride hyperosmolarity to stimulate increase in intestinal endothelial nitric oxide production
https://journals.physiology.org/doi/full/10.1152/ajpheart.00644.2004
Furthermore, it also decreases blood flow to the GI tract..maybe that could be helpful in stopping neurotoxins absorption.
-Stephen
Stephen, it looks individuals with already impaired blood flow to the brain might see negative effects, even though Bumetanide has clear benefits in restoring GABA function to those with NKCC1/KCC2 misexpression.
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