Telmisartan as a useful biological “nudge-therapy,” particularly in bumetanide-responsive autism

 

A nudge is usually better than the sledgehammer !

 

Today’s post is another one most appropriate for people living in autism treatment-friendly counties (Russia, Ukraine, India, USA, Italy, Poland etc). Others will likely see this as from an alternative reality! The post is a bit long, just skip through it. 

My trial dose continues to be 20mg in a 65kg person. Doses trialed in schizophrenia have been much higher. Low doses are always the safest.

The post started life not as a review of any peer-reviewed clinical trials, but rather as an observational report, showing that revisiting the basic science can pay off. I made my initial review several years ago for my own purposes, but shared it in my blog.

I see that in fact the research has partially caught up:

Feinstein Institutes’ scientists find common blood pressure drug could be beneficial in some cases of autism

Scientists at Northwell Health’s Feinstein Institutes for Medical Research have made a significant discovery in autism spectrum disorder (ASD): a widely used blood pressure medication, captopril, can restore healthy function to the brain’s immune cells and reverse ASD-like behaviors in a preclinical animal model. This invaluable research focuses on a specific type of ASD believed to be triggered by a mother’s immune system during pregnancy, and could better understand autism and autism-like symptoms.

 

The full paper is here: 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

 

What this now means - research from 2025 supports Peter’s 2017 idea to use telmisartan for autism

In 2025, researchers at the Feinstein Institutes for Medical Research published a preclinical study showing that modulation of the brain’s renin–angiotensin system (RAS) can reverse autism-like features in a specific immune-primed mouse model. In this model, prenatal immune exposure led to persistent microglial activation, synaptic abnormalities, and altered social behavior — changes that were significantly improved by treatment with captopril, an ACE inhibitor capable of crossing the blood–brain barrier.

Importantly, the study demonstrated that central (brain) RAS signaling is biologically relevant to neurodevelopmental plasticity, and that immune-driven alterations are not necessarily fixed. The benefit was not seen with ACE inhibitors lacking brain penetration, highlighting the importance of central rather than purely peripheral effects.

While captopril was used as a proof-of-concept tool, the underlying mechanism strongly supports the rationale for angiotensin receptor blockers (ARBs) — particularly telmisartan — which offer several advantages. Telmisartan directly blocks AT1 receptors, preserves potentially beneficial AT2 signaling, has a long half-life, and exerts additional anti-inflammatory, metabolic, and mitochondrial effects that are highly relevant to common autism subtypes involving neuroinflammation, behavioral rigidity, fatigue, and impaired stress resilience.

Thus, although the 2025 study does not establish a clinical treatment for autism, it independently validates the systems-level reasoning behind using telmisartan as a chronic “nudge” therapy in carefully selected autism phenotypes. The research supports the mechanism Peter proposed years earlier: that gently modulating regulatory systems such as the brain RAS can restore function in plastic but dysregulated neurodevelopmental circuits.

 

The keep it simple approach

I set out a very simple of framework of classic (Level 3) autism many years ago in this blog. It is also in my book and some presentations.

 

Today’s post falls in to the “central hormonal dysfunction” category.

Renin and angiotensin are both hormones

For the brain, angiotensin (especially angiotensin II) is the one that really matters. Renin is mostly just the upstream trigger.

The brain has its own local renin–angiotensin system, partly independent of the circulating one.

 

A recap for the science lovers - Angiotensin II in the brain

Angiotensin II is the active signalling molecule that actually does things in neural tissue:

• Acts as a neuromodulator
• Shapes excitatory–inhibitory balance
• Influences dopamine, GABA, glutamate
• Regulates stress, threat detection, motivation
• Affects neuroinflammation, oxidative stress
• Alters plasticity and myelination

All of that happens via angiotensin receptors, mainly AT1 and AT2.

 

In the brain, which receptor is activated matters more than how much angiotensin is around:

AT1 receptor (problematic when dominant)

• Increases stress signalling
• Promotes neuroinflammation
• Increases sympathetic tone
• Worsens cognitive rigidity

AT2 receptor (generally protective)

• Promotes neurite growth
• Supports learning and repair
• Anti-inflammatory
• Pro-plasticity

This is why ARBs (especially telmisartan) are interesting neurologically:

• They block AT1
• They shunt signalling toward AT2
• They act inside the brain, not just on blood pressure

 

Back to the more readable stuff

When treating broader autism you can consider the 150-200 possible therapies as ranging from small nudges in the right direction, to a precise hit with a mallet that corrects a precise dysfunction (a specific ion channel dysfunction, a lack of folate in the brain) to a sledge hammer that affects the entire brain (potassium bromide, as an example).

If you have epilepsy and severe aggression then a sledgehammer may well be what you need.

When I first trialed Telmisartan many years ago, I saw that it had an immediate effect, but back then I did not see it as being big enough. It certainly was a nudge, but I was still looking for that mallet, or indeed a sledgehammer. So I moved on.

Last year I revisited Telmisartan and now it is a core therapy. I am happy to include nudge therapies.  

If you have mild autism then a nudge or two maybe all that you need to overcome troubling issues.

If you follow my polytherapy approach for severe autism, then you might select a few nudge therapies and some stronger ones to create a personalized optimization.

 

Telmisartan

Telmisartan is an ARB (angiotensin II type-1 receptor blocker) commonly used to lower blood pressure. But, Telmisartan is thought of best understood not as a single-target drug, but as a system-level regulator.

Telmisartan is highly fat soluble (lipophilic) so it can penetrate the brain and even your bones. Bones matter for old people and all people with level 3 autism.  

Bones are a weak point in severe autism due to the side effects of drugs commonly used, poor diet, lack of exercise and specific genetic issues (in some monogenic autisms).

Bone is not inert. It has active RAAS signalling, telmisartan reaches bone tissue and blocks local AT₁ signalling, reduces inflammatory and oxidative tone in bone microenvironments. Via PPAR-γ, can influence osteoblast/osteoclast balance improving bone density

So an unexpected nudge towards stronger bones. 

The core actions

• AT₁ receptor blockade (RAAS modulation)
  Reduces chronic angiotensin II signalling, lowering background stress, sympathetic drive, and neurovascular strain.
• PPAR-γ partial agonism
  Improves metabolic efficiency, mitochondrial function, and lipid–glucose handling; contributes to anti-inflammatory effects.
• Autonomic calming
  Lowers sympathetic tone and stress reactivity without sedation. This a nudge effect towards better sleep, in some people
• Anti-inflammatory and antioxidant effects
  Indirectly reduces microglial activation and oxidative stress signalling. Microglia are the brain’s immune cells and can be in state of constant activation, which blocks them doing their basic housekeeping duties.
• Neurovascular effects
  Improves cerebral blood flow regulation and oxygen–nutrient delivery. In many types of severe autism, and also in dementia, the brain is unable to produce enough fuel (ATP). While there are many possible factors involved a key one is delivery of glucose and oxygen from your blood.

 

Indirect downstream effects (relevant to neurodevelopment)

• Improved cellular energy status
  Supports ion-pump function and transporter regulation. This is a nudge by improving the environment, Telmisartan does not force the ion-pumps directly
• Stabilisation of chloride homeostasis (indirect)
  Biases the NKCC1–KCC2 balance toward better chloride extrusion in vulnerable circuits, without forcing a gradient shift.

This is the big plus for bumetanide responders

Neuronal chloride levels are set by the balance between NKCC1 (chloride import) and KCC2 (chloride extrusion).

In some with autism the GABA development switch failed to activate after birth and so NKCC1 is overexpressed and KCC2 is under expressed

Stress, inflammation, and high activity increase NKCC1 influence and chloride loading.

KCC2 function is energy- and redox-dependent, and degrades under metabolic strain.

Telmisartan does not directly block NKCC1 or activate KCC2.

By reducing RAAS-driven stress signalling, it lowers pressure toward chloride accumulation.

Improved metabolic and redox conditions stabilise KCC2 membrane function.

Reduced autonomic overdrive lowers activity-dependent chloride loading.

The net effect is a bias toward more reliable chloride extrusion in vulnerable circuits.

This stabilises inhibition without forcing a chloride gradient shift, which KBr the sledgehammer would do. 

• Reduced excitability pressure
  Lowers the likelihood that inhibitory signalling becomes destabilised under stress.

 

Theoretical functional consequences (when it works)

• Lower baseline arousal and irritability
• Improved mood stability
• Increased behavioural flexibility
• Greater tolerance of sensory and cognitive load
• Enhanced availability for learning and interaction

 

My experience

When I conducted my review of “all autism” several years ago I did look at angiotensin. It looked to me that Telmisartan ticked many of the boxes for a cheap generic drug that could be repurposed for autism.

I did trial it and noted an immediate mood improvement with the strange effect of making Monty want to sing.

Several years later trialing it again. Again mood improved, there was no singing, but there was a desire to dance.

It also makes him less rigid. The best example is that when he empties the dishwasher he very clearly now puts things back in different places. You could argue this is negative, or you could see that as expressing his will rather than robotically following a pattern. More on that in the basal ganglia section.

The Basal Ganglia

The basal ganglia is the part of the brain that drives conditions like Tourette syndrome and PANS-PANDAS.

In PANS-PANDAS the immune system temporarily hijacks basal ganglia signalling. This is reversable, with prompt treatment.

The basal ganglia do not generate behaviour.

They gate behaviour.

When basal ganglia inhibition is stable:

• unwanted actions are quietly suppressed  (no tics)
• chosen actions feel voluntary
• habits can be overridden (no autistic rigidity)
• novelty is possible (try new foods, or watch a different cartoon) 

When basal ganglia function is disrupted (by genetics, inflammation, chloride instability, dopamine imbalance, Purkinje cell loss):

• the repertoire of behaviours is still there
• the motor programs still exist
• the thoughts still arise

What is lost is control over which ones fire. This manifest in autism as

Rigidity and stereotypies

• Repetitive behaviours are not “added”
• They become locked in
• Alternative actions cannot pass the gate

The system defaults to what feels safe and known.

This links to 2 further subjects of interest:

·        Purkinje cell loss in severe autism
·        ARFID (Avoidant/Restrictive Food Intake Disorder)

 

Purkinje cell loss as one possible driver of basal ganglia dysfunction

Purkinje cells are the very large, energy-intensive output neurons of the cerebellar cortex, providing continuous inhibitory timing signals to the deep cerebellar nuclei.

During the first two years of life, rapid brain growth creates extreme ATP demand, and transient mitochondrial or metabolic shortfalls can cause brief “power outages.” Because Purkinje cells are among the largest and most metabolically demanding neurons, they are selectively vulnerable and may be lost early, in a patchy and permanent manner. This a classic finding in port-mortem brain studies of people who had severe autism.

Purkinje cell loss leads to clumsiness and dyspraxia, because the cerebellum’s output signal loses timing precision, causing movements to be poorly planned, sequenced, and adjusted despite normal muscle strength. It does not lead to paralysis.

The resulting noisy cerebellar output propagates via thalamocortical loops to the basal ganglia, where it destabilizes action-selection and gating, particularly in the context of immature chloride regulation and weakened GABAergic inhibition.

Although the original cerebellar injury cannot be reversed, downstream circuits remain plastic, allowing pharmacological “nudges” such as bumetanide, atorvastatin, and telmisartan to partially restore inhibitory precision, improve basal ganglia gating, and reopen a window of motor-cognitive flexibility.

 

ARFID (Avoidant/Restrictive Food Intake Disorder)

ARFID can be the feeding expression of the same underlying circuit problem.

The framework explains ARFID extremely well, especially the autism-associated form of ARFID. In fact, it explains it better than sensory-only models. 

ARFID through the basal ganglia “gate” lens

Repetitive behaviours are not added — they become locked in.
Alternative actions cannot pass the gate.
The system defaults to what feels safe and known.

That description fits ARFID almost perfectly. 

In autism and related neuroimmune states, ARFID often acts as a behavioural marker of basal ganglia gating dysfunction, reflecting loss of choice rather than loss of appetite.

ARFID is not always basal ganglia–driven.

There are other ARFID subtypes:

• trauma-based (choking/vomiting)
• primary sensory aversion
• gastrointestinal pain–avoidance
• appetite dysregulation from meds or illness

But in autism-associated ARFID, especially when it:

• fluctuates with stress or illness
• coexists with rigidity, tics, OCD traits
• improves alongside mood and flexibility

the basal ganglia model fits extremely well. 

Blunt pharmaceutical treatment (sledgehammer) of ARFID does not work. Nudges seem a better choice. Nudges can be behavioral, or biological. 

Beyond telmisartan, the most promising pharmaceutical nudges for ARFID are likely those that reduce immune and autonomic stress on basal ganglia circuits while preserving motivation and behavioural flexibility, rather than suppressing output.

Many autism interventions provide a nudge to better functioning of the basal ganglia (NAC, ALA, low dose clonidine, atorvastatin etc).

Indeed one notable immediate effect of atorvastatin on Monty 14 years ago, was that he starting to come downstairs from his bedroom by himself, and not get “stuck” at the top of the stairs awaiting instructions.

I used to call this cognitive inhibition, but perhaps the gating model explains it better.

 

What the behaviour actually shows

“Stuck at the top of the stairs awaiting instructions”
is not a strength or balance problem.

It reflects:

• failure of self-initiated action
• dependence on external cueing (prompt dependence, in ABA terminology)
• intact ability, but blocked execution

That already points away from motor cortex and toward action-selection systems.

 

Basal ganglia explanation

Basal ganglia = action gating, not movement generation

The basal ganglia decide:

• when an action is allowed to start
• whether it is safe to proceed without prompting

In autism (and related neuroimmune states), this gate can become over-conservative:

• “wait”
• “don’t move”
• “need instruction”

So the child:

• knows how to go downstairs
• but cannot release the action independently

 

Why stairs are a perfect stress test

Descending stairs requires:

• motor sequencing
• balance prediction
• suppression of fear/uncertainty
• confidence in outcome

Basal ganglia dysfunction often shows up first in:

• transitions
• initiation
• descending movements
• unprompted actions

So “stuck at the top of the stairs” is a classic gating failure.

 

Why atorvastatin could change this quickly

Atorvastatin did not:

• teach a new skill
• strengthen muscles
• improve coordination

What it plausibly did was reduce a state constraint.

Immune / inflammatory relief

If there was:

• low-grade neuroinflammation
• immune-driven basal ganglia noise

Then dampening that can:

• lower threat signalling
• stabilise dopamine–GABA balance
• relax excessive inhibitory gating

When that happens:

actions that were already available suddenly “go.”

That can be rapid.

 

Reduced “protective inhibition”

In stressed systems, the brain sometimes actively prevents independence:

• to avoid risk
• to avoid uncertainty

Once the stress signal drops, the system stops applying the brake.

This feels like:

• confidence
• initiative
• independence

 

Why instruction dependence disappears

Needing instruction is a workaround:

• the external cue substitutes for internal gating
• the basal ganglia borrow cortical direction

When gating improves:

• the workaround is no longer needed
• behaviour becomes self-initiated

This is not just basal ganglia

Other systems likely contributed:

Cerebellum

• prediction of movement outcome
• timing and sequencing
• fear of misstep

Cerebellar function improves when:

• inflammation drops
• prediction error decreases

Autonomic system

• high sympathetic tone increases “freeze”
• calming allows movement initiation

Confidence loop

• once one successful descent occurs
• future attempts are easier
• habit loop updates

But the gatekeeper is still basal ganglia.

 

Conclusion

The basal ganglia are not “movement centres” in the simple sense.
They are action–selection and state–selection systems.

They decide:

• which action to initiate
• when to initiate it
• whether to repeat the same pattern or explore a new one
• how much reward, pleasure, and motivation is attached to action

They sit at the junction of:

• movement
• mood
• motivation
• habit
• flexibility

That is why basal ganglia changes show up as movement + emotion + novelty, all together.

 

Basal ganglia are especially sensitive in autism

Basal ganglia circuits:

• are GABA-heavy
• are chloride-sensitive
• rely on finely balanced inhibition
• are vulnerable to stress, inflammation, and metabolic strain

When inhibition in these circuits is unstable:

• action initiation becomes effortful
• behaviour becomes repetitive and rigid
• novelty feels unsafe
• mood flattens or becomes anxious

What changed biologically (without forcing anything)

When inhibition becomes more reliable (not stronger, just more predictable):

• neurons fire when they should, not erratically
• “gating” improves and actions can pass through more smoothly
• reward signals are no longer drowned out by noise

 

Why did Monty become happier

Mood is not just cortical thought, it is basal ganglia tone.

With better inhibitory stability:

• dopamine signalling becomes cleaner
• reward prediction improves
• the background “threat” signal drops

The result is:

• spontaneous positive affect
• relaxed facial expression
• joy without obvious cause

This is state change, not learned happiness.

 

Why the urge to dance appears

Dancing is a near-perfect basal ganglia readout.

It requires:

• effortless movement initiation
• rhythmic pattern generation
• reward linked directly to motion

When basal ganglia output is constrained:

• movement feels heavy
• initiation is delayed
• spontaneous rhythm disappears

When the constraint lifts:

• movement becomes intrinsically rewarding
• the body “wants” to move
• rhythm emerges without instruction

That is why dancing appears before language or cognition improves.

 

Why he emptied the dishwasher differently

Changing how a familiar task is done means:

• the brain is no longer locked into a single motor–habit template
• alternative action sequences are now selectable
• exploration feels safe

This is classic basal ganglia flexibility.

Nothing taught him that new method.

The system simply allowed another option to pass through the gate.

 

 

 

Autism + PANDAS/PANS ? - Basal ganglia circuitry mechanism underlying some repetitive behaviour

Pu-erh, a fermented tea from Yunnan province, China.  An mGluR5 inhibitor to remedy basal ganglia circuit abnormalities?

PANDAS/PANS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections/Pediatric Acute-onset Neuropsychiatric Syndrome) are recognized disorders in North America, but nowhere else.  If you take your child to Boston Children’s Hospital and ask about PANDAS they will know what you are talking about, try this at a children’s hospital in Europe and you will be directed to the local zoo.

For those new to the subject PANDAS/PANS cause sudden onset of tics and Obsessive Compulsive Disorder (OCD) accompanied by sudden cognitive regression.

I have written about PANDAS/PANS in previous posts.

PANDAS, PANS, Penguins and Autism

I was surprised how well documented these syndromes are and that they are treated by some mainstream physicians.

The leading researcher in the field, Susan Swedo, makes a point that PANDAS/PANS is not autism.  I think that given the ever broadening definition of what counts as autism, it should be considered as a treatable sub-type of regressive autism.

To what extent can people with classic early onset autism also have PANDAS/PANS is an open question.

Can you have both?  Well based on my n=1 experience, it looks like you can.

After a brief infection just before Christmas, Monty aged 13 with classic early onset autism, suddenly developed Tourette’s-like loud verbal tics.  This behaviour had never occurred before and erupted overnight.  Even his brother declared that Monty now has Tourette’s and when would it go away.  This is the kind of behavior that many siblings, and I suppose some parents, would find extremely embarrassing.

Having a blog jam-packed with information on autism and related issues, I thought this was another problem that I should solve myself.  

On one of Harvard’s blogs it says regarding PANDAS/PANS symptoms:-

If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.

Well none of that advice was an option for me, but I do think that early treatment is key in neurological disorders.  This also applies to people with autism developing seizures, where I think pre-treatment can lead to never developing seizures.

So I decided I would treat Monty as if he was having PANDAS flare-up.  This entails antibiotics and a short course of steroids.  The alternative was to do nothing and hope it just all went away.

Monty very rarely has antibiotics; his immune system seems very effective and quite possibly overly effective.

Having had a severe asthma attack several years ago we have prednisone on hand.  Oral prednisone is a cheap generic steroid drug that can be used as therapy for an asthma attack that does not respond to the usual inhaler treatment.  Long term use of prednisone has significant side effects and therapy longer than a few days requires you to taper the dose.

Having started the therapy, the loud random verbal tics continued for a few days and then faded away to zero over a couple of weeks.

Would this have happened without Amoxicillin and Prednisone?  I have no means of knowing, but I agree with Monty's big brother, we do not want to have Tourette’s/PANDAS/PANS in addition to autism.

Therapy started within two days of the tics.

Can an infection suddenly cause OCD?

If your child suddenly shows any of these symptoms, call your doctor as soon as you can. Then contact the International OCD Foundation to find an OCD specialist in your area. Early treatment may prevent life-long mental illness.

and an interesting comment on that same Harvard blog:-

“PANDAS and autism is very common. My son has both. When we can get his PANDAS under control, his autism is almost nonexistent. He has been diagnosed with PDD-NOS, which is atypical autism. PANDAS antibodies can also attack other areas of the brain if the infection gets out of control. People need to be aware of this. Untreated strep would result in my son regressing further into autism. If you have looked into Saving Sammy, you’ll notice he stopped responding, like many autistics, and that some of his repetitive behaviors could be considered similar to stimming.

With my son, he also gets repetitive movements and OCD, but ADHD symptoms, major defiance and extreme outbursts, threats of violence, etc.

More doctors of autistic kids need to screen them for PANDAS.”

PANDAS and Tourette’s Syndrome

There is a debate over whether PANDAS/PANDAS is just Tourette’s syndrome.

This is where you need to know the difference between the tic type of compulsive behavior and the repetitive behavior that is stimming/stereotypy.  They are not the same and do not respond to the same therapies.

In this blog I do refer to Tourette’s-type autism.  This is one type of autism that research shows can just fade away.

Inflammatory Response to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)

 

Pediatric Autoimmune Disorders Associated with Streptococcal Infections and Tourette's Syndrome in Preclinical Studies

Accumulating evidence suggests that Tourette's Syndrome (TS) – a multifactorial pediatric disorder characterized by the recurrent exhibition of motor tics and/or vocal utterances – can partly depend on immune dysregulation provoked by early repeated streptococcal infections. The natural and adaptive antibody-mediated reaction to streptococcus has been proposed to potentially turn into a pathological autoimmune response in vulnerable individuals. Specifically, in conditions of increased permeability of the blood brain barrier (BBB), streptococcus-induced antibodies have been proposed to: (i) reach neuronal targets located in brain areas responsible for motion control; and (ii) contribute to the exhibition of symptoms. This theoretical framework is supported by indirect evidence indicating that a subset of TS patients exhibit elevated streptococcal antibody titers upon tic relapses. A systematic evaluation of this hypothesis entails preclinical studies providing a proof of concept of the aforementioned pathological sequelae. These studies shall rest upon individuals characterized by a vulnerable immune system, repeatedly exposed to streptococcus, and carefully screened for phenotypes isomorphic to the pathological signs of TS observed in patients. Preclinical animal models may thus constitute an informative, useful tool upon which conducting targeted, hypothesis-driven experiments. In the present review we discuss the available evidence in preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), and the existing gaps that future research shall bridge. Specifically, we report recent preclinical evidence indicating that the immune responses to repeated streptococcal immunizations relate to the occurrence of behavioral and neurological phenotypes reminiscent of TS. By the same token, we discuss the limitations of these studies: limited evidence of behavioral phenotypes isomorphic to tics and scarce knowledge about the immunological phenomena favoring the transition from natural adaptive immunity to pathological outcomes.

Basal Ganglia and SAPAP3 gene

It is suggested that PANDAS is caused by group A beta-hemolytic streptococcal (GABHS) infections. The proposed link between infection and these disorders is that an initial autoimmune reaction to a GABHS infection produces antibodies that interfere with basal ganglia function.

Many other disorders that are often comorbid with autism are also linked to the basal ganglia, such as tics, stuttering, Tourette’s and even tardive dyskinesia caused by inappropriate treatment of autism with antipsychotics.

The following is a list of disorders that have been linked to the basal ganglia

• Addiction
• Athetosis
• Athymhormic syndrome (PAP syndrome)
• Attention-deficit hyperactivity disorder (ADHD)
• Blepharospasm
• Bruxism
• Cerebral palsy: basal ganglia damage during second and third trimester of pregnancy
• Chorea
• Dystonia
• Fahr's disease
• Foreign accent syndrome (FAS)
• Huntington's disease
• Kernicterus
• Lesch–Nyhan syndrome
• Major Depressive Disorder
• Obsessive-compulsive disorder
• Other anxiety disorders
• PANDAS
• Parkinson's disease
• Spasmodic dysphonia
• Stuttering
• Sydenham's chorea
• Tardive dyskinesia, caused by chronic antipsychotic treatment
• Tourette's disorder
• Wilson's disease

 Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Basal ganglia circuits underlying repetitive behaviors in autism

Repetitive behaviors are common in several neuropsychiatric disorders, including obsessive-compulsive disorders and autism spectrum disorders. Guoping Feng and his team are investigating the pathological mechanisms underlying repetitive behaviors, with the aim of understanding the neural mechanisms and genetic factors that cause or contribute to autism.

The team’s previous studies in mice show that deletion of the SAPAP3 gene, which is implicated in obsessive-compulsive disorders, leads to repetitive behaviors¹. The gene’s deletion leads to defective neuronal communications in the basal ganglia, a brain region known to be involved in voluntary movement.

There are two circuits within the basal ganglia, known as the direct and indirect pathways. Feng’s group generated transgenic mice in which SAPAP3 expression can be selectively turned on or off in these two pathways. They found that selective re-expression of SAPAP3 in the direct pathway of the basal ganglia completely reverses the repetitive behavior seen in mice lacking SAPAP3. This effect is not seen in the indirect pathway, indicating that the two pathways play different roles in the pathogenesis of repetitive behavior.

Feng’s group also studied SHANK3, which interacts with SAPAP3 protein in the basal ganglia. SHANK3 mutations are strongly linked to an autism spectrum disorder called Phelan-McDermid syndrome². The researchers found that deletion of the SHANK3 gene in mice leads to repetitive behaviors similar to those seen in mice lacking SAPAP3³. Importantly, the researchers discovered similar neuronal communication defects in the basal ganglia of SHANK3 and SAPAP3 mutant mice. Together, these results provide strong evidence for a common basal ganglia circuitry mechanism underlying repetitive behavior⁴

Study Points to Fast-Acting Drug for OCD

In the new study, Calakos’s team found that overactivity of a single type of receptor for neurotransmitters -- mGluR5, found in a brain region involved in compulsive behaviors -- was the major driver for the abnormal behaviors. When researchers gave Sapap3-lacking mice a chemical that blocks mGluR5, the grooming and anxiety behaviors abated.

“The reversibility of the symptoms was immediate -- on a minute time frame,” Calakos said. In contrast, the original study describing Sapap3-lacking mice found that antidepressants could help treat symptoms but on the time scale of weeks, as is typical with these drugs in patients.

Intriguingly, by taking normal laboratory mice and giving them a drug that boosted mGluR5 activity, Calakos’s team could instantaneously recreate the same excessive grooming and anxiety behaviors they saw in the Sapap3-lacking mice.

The researchers found that without a functioning Sapap3 protein, the mGluR5 receptor is always on. That, in turn, makes the brain regions involved in compulsion overactive. In particular, a group of neurons that give the “green light” for an action, like face-washing, is working overtime. (These same neurons can promote a habit, such as eating sweets, according to a study published by Calakos’s team earlier this year.)

Calakos said that mGluR5 should be considered for the treatment of compulsive behaviors. “But which people and which compulsive behaviors? We don’t know yet,” she added. 

Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

Conclusions

These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.

Diagnostic Tests for PANDAS/PANS

Madeleine Cunningham, who used to work at the NIMH researching PANDAS with Susan Swedo, went off to set up a company to promote her “Cunningham Panel” of tests.

The Panel consists of 5 tests which measure circulating levels of autoantibodies directed against specific neuronal antigens in the patient including: Dopamine D1 Receptor (DRD1), Dopamine D2L Receptor (DRD2L), Lysoganglioside – GM1 and Tubulin. The 5th assay targets CaM Kinase II, a key enzyme involved in the up regulation of many neurotransmitters (dopamine, epinephrine, norepinephrine).

The Cunningham Panel

In the United States, 6.4 million children have received an ADHD diagnosis; 50% of all children with the disorder are diagnosed by age 6. Meanwhile, one million children have been diagnosed with Autism Spectrum Disorder ¹ and 500,000 children are living in the U.S. with OCD.

Identifying the underlying cause of these symptoms is imperative and answering the following question could change the course of treatment: ‘Could an infection be causing my child’s symptoms?’ Children may be misdiagnosed with a primary psychiatric disorder and receive psychotropic medications to treat the symptoms. But if the symptoms are due to an infection-triggered autoimmune response, the root cause of the behaviors must be addressed. Treatment must include eradicating the infection (if possible) and addressing the immune dysfunction.

                                                                                       

Treatments for PANDAS

Treatments for PANDAS are not yet well-studied as this condition has only recently been identified. Conventional treatments may include oral antibiotics to eradicate a Streptococcal infection, and prophylactic antibiotics to prevent recurrence. Oral prednisone is also used as a potent anti-inflammatory to relieve inflammation of the brain and prevent damage. Another therapy known as intravenous immunoglobulin (IVIG) is being investigated.

Intravenous glutathione, a potent antioxidant, can be used to protect the brain from being damaged from inflammation.

NIMH- Information About PANDAS

PANDAS Physicians Network

Time for Tea?

If you read the SAPAP3 research above, a totally different type of therapy might also improve OCD disorders stemming from the basal ganglia; you would try inhibiting metabotropic glutamate receptor 5 (mGluR5).

Given many people’s aversion to drugs, they might want to brew up some Pu-erh tea.  This type of tea is widely used for weight loss.  It should also reduce your cholesterol.

Pu-erh Tea Protects the Nervous System by Inhibiting the Expression of Metabotropic Glutamate Receptor 5.

Glutamate is one of the major excitatory neurotransmitters of the CNS and is essential for numerous key neuronal functions. However, excess glutamate causes massive neuronal death and brain damage owing to excitotoxicity via the glutamate receptors. Metabotropic glutamate receptor 5 (mGluR5) is one of the glutamate receptors and represents a promising target for studying neuroprotective agents of potential application in neurodegenerative diseases. Pu-erh tea, a fermented tea, mainly produced in Yunnan province, China, has beneficial effects, including the accommodation of the CNS. In this study, pu-erh tea markedly decreased the transcription and translation of mGluR5 compared to those by black and green teas. Pu-erh tea also inhibited the expression of Homer, one of the synaptic scaffolding proteins binding to mGluR5. Pu-erh tea protected neural cells from necrosis via blocked Ca²⁺ influx and inhibited protein kinase C (PKC) activation induced by excess glutamate. Pu-erh tea relieved rat epilepsy induced by LiCl-pilocarpine in behavioural and physiological assays. Pu-erh tea also decreased the expression of mGluR5 in the hippocampus. These results show that the inhibition of mGluR5 plays a role in protecting neural cells from glutamate. The results also indicate that pu-erh tea contains biological compounds binding transcription factors and inhibiting the expression of mGluR5 and identify pu-erh tea as a novel natural neuroprotective agent.

Scientific studies report that consumption of pu-erh tea leaves significantly suppressed the expression of fatty acid synthase (FAS) in the livers of rats; gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed. The compositions of chemical components found to have been responsible for these effects (catechins, caffeine, and theanine) varied dramatically between pu-erh, black, oolong, and green teas.

Pu-erh tea supplementation suppresses fatty acid synthase expression in the rat liver through downregulating Akt and JNK signalings as demonstrated in human hepatoma HepG2 cells.

Fatty acid synthase (FAS) is a key enzyme of lipogenesis. Overexpression of FAS is dominant in cancer cells and proliferative tissues. The expression of FAS in the livers of rats fed pu-erh tea leaves was significantly suppressed. The gains in body weight, levels of triacylglycerol, and total cholesterol were also suppressed in the tea-treated rats. FAS expression in hepatoma HepG2 cells was suppressed by the extracts of pu-erh tea at both the protein and mRNA levels. FAS expression in HepG2 cells was strongly inhibited by PI3K inhibitor LY294002 and JNK inhibitor II and slightly inhibited by p38 inhibitor SB203580 and MEK inhibitor PD98059, separately. Based on these findings, we suggest that the suppression of FAS in the livers of rats fed pu-erh tea leaves may occur through downregulation of the PI3K/AKt and JNK signaling pathways. The major components of tea that have been demonstrated to be responsible for the antiobesity and hypolipidemic effects are catechins, caffeine, and theanine. The compositions of catechins, caffeine, and theanine varied dramatically in pu-erh, black, oolong, and green teas. The active principles and molecular mechanisms that exerted these biological effects in pu-erh tea deserve future exploration.

Conclusion

Sudden onset tic disorder associated with loss of cognitive function does seem to be a distinct dysfunction. Fortunately it is being well researched.

Whether antibodies, due to an infection, crossing the blood brain barrier and causing chronic inflammation in the basal ganglia is the cause remains unproven, but seems plausible.

Exactly what kinds of infections can trigger this response is an open question.  The people selling the PANDAS/PANS diagnostic test, the Cunningham panel, suggest that a wide range of both viral and bacterial infections can trigger this reaction.  As is often the case, there may be a case of some over diagnosis and very expensive use of IVIG therapy.  No test will be perfect because the area is highly subjective.

A recent paper reconfirmed the view that both the blood brain barrier and the intestinal barrier can be compromised in autism.

Study finds alterations in both blood-brain barrier and intestinal permeability inindividuals with autism

Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

This suggests that all kinds of things might be crossing the blood brain barrier.

As we have seen, autism seems to be usually caused by multiple hits, rather than a single gene dysfunction, but we have also seen that in cases of severe autism there can be a step-change regression from earlier moderate autism to severe autism.  I called this double-tap autism, so as not to confuse with multiple hits. 

In double-tap autism things usually start out quite well, with good response to behavioral therapy, in early years, and then take a nose dive and can spiral completely out of control leading to institutionalization.

We have seen cases where the second tap/event is immune related and others where it is the onset of seizures around puberty, but usually the trigger remains unidentified.

I would imagine that PANDAS/PANS could also be such a second tap/event.  The issue is not just the tics/OCD but the associated loss of cognitive function. Given that immediate intervention has been shown to be highly effective in PANDAS/PANS, before the condition has become chronic and much less responsive, it would be wise for more people to be aware of what can be done.

Will some Chinese tea affect mGluR5 in a good way?  It remains to be seen; these receptors are present in different parts of the brain where they have opposing functions.  mGluR5 is a target of autism research at MIT and was covered in earlier posts. Here is another link:-

Picower Institute researchers show that different causes of autism and intellectual disability respond to the same treatment

It may be necessary to have a brain region specific mGluR5 inhibitor.

We can add Pu-erh tea to the growing list of things that reduce cholesterol - cinnamon, pantethine (active form of vitamin B5), sytrinol etc.  Interestingly 600mg of pantethine lowers cholesterol but increases coenzyme Q10 (statins reduce coenzyme Q10).  Pu-erh tea actually has some naturally lovastatin in it, but that may not be its main mode of lowering cholesterol .