Mouse Models of Autism

Researchers use animals in place of humans, for research purposes; in the case of autism it is usually the unfortunate mouse, but sometimes rats. 

The Jackson Laboratory in the US is the source for more than 8,000 strains of genetically defined mice used for research purposes.   

SFARIgene has a fascinating on-line database  that lists all the mouse/rat models of autism and the research linked to them. Most importantly it also lists all the “rescue lines”, the research showing therapies that improved the mouse’s autism. 

For example, you can look up the model of human Fragile-X, which is called Fmr1, and then see the long list of drugs that helped that particular type of mouse. 

There are already well over 200 different mouse/rat genetic models of autism and 1,000 rescue lines.  

So while medicine has no approved drugs to treat human autism, autistic mice appear to be better placed.

There remains the question of how close humans are to mice.  They are more closely related than you might think, but there are still big differences. 

There are also induced models of autism, where the scientists have not tinkered with a specific single gene; these might closer relate to most human autism. You will find a model of advanced paternal age, a model of diesel exhaust particles, and all kinds of other things. 

One very widely used model is called the Maternal Immune Activation (MIA) model.  In the research you may find it called Polyinosinic:polycytidylic acid, or just poly(I:C).

 In the MIA model the pregnant mouse is injected will an immune stimulant (Polyinosinic:polycytidylic acid) that triggers a big immune response, which affects the development of her pup.  The pup is born with features that resemble human autism. 

There is a similar model where the mother is given an infection rather than induced inflammation. 

Depending on the gestational age at which MIA or infection is administered, the offspring can be studied in the context not only of autism, but also schizophrenia.  This should not be surprising if you have read the post discussing the overlapping polygenic nature of autism and schizophrenia. 

You can even induce temporary autism using proprionic acid.  Proprioic acid is produced naturally in your intestines when the food you eat reacts with the bacteria that live there.  Proprionic acid is a SCFA (short chained fatty acid), you need to have some SCFAs, but as it often the case, too much may not be good for you.  In the case of a mouse, when injected with a large dose of poprionic acid, its behaviour changes to that of autism.  This is entirely reversible over time, or faster still, by administering the antioxidant NAC (N-acetyl cysteine). 

Researchers create a mouse model that matches as closely as possible the human condition they are trying to treat. Then they can investigate various drugs that might be of therapeutic benefit.  In some cases a large number of drugs from a library of compounds are tried on the off chance of stumbling upon one that is effective. 

An alternative approach is when a researcher has a theory that a specific drug should be effective, he then tests it in several different mouse models of autism.  If the drug is effective in several mouse models that would suggest it might be beneficial in some humans. This is how Ben-Ari advanced his bumetanide research and Catterall his low dose Clonazepam research; the difference is that Ben-Ari has moved on to humans, as regular readers know.  

Those of you who look at the SFARgene database will see how hundreds of so very different things, both genetic or environmental, lead to the same autism.

The Brain is Hypothermic in Mitochondrial Disease, but is it in Autism?

Having noted in the previous post something as simple, and measurable, as reduced blood flow in the brain exists in autism, I decided to dig a little deeper.

Not only can you measure blood flow in specific regions of the brain, but using Magnetic Resonance Spectroscopy you can measure the temperature of the brain.

Intense heat production is an essential feature of normal brain energetics; most of the energy used for brain functioning is eventually released as heat.  In the brain, heat is produced mostly by mitochondrial oxidative chemical reactions. Most of the energy required for brain activity is generated from the net chemical reaction of oxygen and glucose; some of this energy (33%) is immediately dissipated into heat, and the rest (67%) is used to synthesize ATP. The final ATP hydrolysis releases part of the energy back to the system as heat.

Note that your core temperature is not the same as your brain temperature.

Brain temperature T_br should be near constant

Increases in Cerebral Blood Flow reduce T_br and increases in brain metabolism increase T_br.

Neuronal activity is temperature dependent, with neuronal firing increasing with increased temperature.  Many other functions in the brain are temperature dependent.

When your brain gets too hot febrile seizures can be the result, caused by excessive neuronal firing.

Mitochondrial Disease

Since heat in the brain is produced mostly by mitochondrial oxidative chemical reactions, when mitochondrial disease is present, it would be expected that there would be less heat and therefore a lower Brain temperature T_br.  This time biology is indeed logical and this is the case.  People with mitochondrial disease have measurably colder brains.

The brain is hypothermic in patients with mitochondrial diseases

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

The question is whether this lower brain temperature, in itself, leads to changes in brain function/performance and hence mood, behaviours and cognition.

Mitochondrial Disease in Autism

There are various types of mitochondrial disorder in autism and, confusingly, different terminology is used for similar biological conditions.  Regressive autism triggered by a viral illness, fever, or in some cases a reaction to a vaccine is likely mitochondria-related.

I have covered Dr Kelley from Johns Hopkins ideas on this subject, but there are others.  Here are some other perspectives:-

Has Your Child with Autistic Symptoms Been Properly Screened for a Subset of  Mitochondrial Disease Known as OXPHOS?

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

Fever Effect in Autism

It is well documented that in many people with autism their symptoms subside when they are sick and have a fever.  This is the so-called “fever effect”.  It only applies to some people with autism and in a small number the effect can be dramatic.

There are numerous unproven theories.

A Study of Behaviors Associated with Fever in Children with Autism/PDD

Hyperthermia and the amelioration of autism symptoms 

  

Hyperthermia and the Improvement of Autism Spectrum Disorder (ASD) Symptoms

Background:  The observation that some ASD patients manifest clinical improvement in response to fever suggests that symptoms may be modulated by immune-inflammatory factors.  The febrile hypothesis of ASD stems from this observation, and could be due to (1) the direct effect of temperature; (2) a resulting change in the immune inflammatory system function associated with the infection of fever; and/or (3) an increase in the functionality of a previously dysfunctional locus coeruleus-noradrenergic (LC-NA) system.  

Objectives:  To assess the effect of hyperthermia on ASD symptoms.

Methods:  We completed a double blind crossover study of 15 children with ASD (5 to 17 years) using two treatment conditions, hyperthermia condition (102°F) and control condition (98°F) in a HydroWorx aquatic therapy pool.  Five children with ASD without fever response acted as controls, completing only the hyperthermia condition, to ensure safety and feasibility.  Safety measures and Social Responsiveness Scale (SRS) were collected.  Ten patients with ASD and history of fever response were enrolled and received both treatment conditions.  Vital signs, temperature monitoring and clinical observations were completed throughout their time in the pool.  Parents completed the SRS and RBS-R.  Pupillometry biomarker and buccal swabs for DNA and RNA extraction were collected pre and post pool entry. 

Results:  Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102°F) and control condition (98°F) at the aquatic therapy pool.  Improvement during the hyperthermia condition (102°F) was observed in social cognition, using the Social Responsiveness Scale (SRS) total raw score (p = 0.0430) and the SRS Social Behavior subscale raw scores (p = 0.0750); repetitive behaviors, using the Repetitive Behavior Scale-Revised (RBS; p =0.0603) and the SRS Restricted and Repetitive Behavior subscale (p = 0.0146); and on global improvement, using the Clinical Global Impression Scale-Improvement (CGI-I; p=0.0070). 

Conclusions:  This study demonstrates the feasibility of observing the direct effect of temperature in children with ASD, both with and without a history of febrile response, and provides preliminary data on the relationship between body temperature and changes in social and behavioral measures. It explores the direct effects of temperature on ASD symptoms, and offers a window into understanding mechanisms involved in improvement in ASD symptoms during fever episodes.  Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. This study is important for the development of translational models on the mechanism of symptom improvement and the identification of novel targets for therapeutic development.

Why not measure Brain temperature T_br in a large number of people with Autism?

The above study at the “Albert Einstein” medical school involved putting people in hot tubs to warm them up and then measuring their autistic symptoms. You would have thought it would have occurred to them to quickly pop upstairs to the MRI to measure brain temperature T_br.  I do not think you need to be an Einstein to think of that.

Perhaps the people that exhibit the fever effect are the ones with low brain temperature T_br ?  That would seem well worth checking.

It also is logical to just warm up the part of the body that will affect behaviour.

Hypothermia in Mouse Models

If you look up hypothermia and autism you again encounter Robert Naviaux, from University of California San Diego, and not much else.  Naviaux is a very clever researcher, but more importantly he just does not give up.  He is doggedly pursuing his antipurinergic therapy for autism.

It turns out that hypothermia is a feature of the maternal immune activation (MIA) mouse model of autism that he is using in his research.

Indeed his antipurinergic therapy corrects this hypothermia.

From:-

Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model.

Relative hypothermia is a long-term feature of the Poly(IC) MIA Model. This is the lower line (PICSAL), when treated with Suramin, you get the yellow line PICSUR, with a higher body temperature similar to that of the regular mice (blue lines)  When they gave Suramin to regular mice (dark blue line) the was no overall change in body temperature.

So we know that in at least one major mouse model of autism, hypothermia is known feature.  Did anyone measure it in the others?

Conclusion

If raising T_br improves autism symptoms so much, in some people, then why not just figure out a clever way to increase it?

Raising blood flow apparently should lower T_br.

There are likely numerous options like increasing the oxygen level in the blood, which might be expected to increase heat production, for example using Diamox (Acetazolamid). 

Reducing heat loss by wearing a wooly hat, should marginally raise brain temperature, unless the brain then compensates for this.

Since the illicit drug MDMA, or ecstasy, is already known to raise brain temperature, there probably are ways to develop a safe drug therapy to achieve a small increase in brain temperature.  

  

Hopefully Naviaux will find a safe antipurinergic therapy, which might also be used in people with low T_br, as well as broader autism.