Autism: Birth hormone controls the expression of the syndrome in animals

Researchers found that a drug affecting chloride levels improves autistic-like behaviour in offspring of mouse models of autism. 

The drug restores the so-called GABA switch in the neurons of fetal mice when given to the mother one day before delivery. 

Credit: D.C. Ferrari

The scientific community agrees that autism has its origins in early life—foetal and/or postnatal.

The team led by Yehezkel Ben-Ari, Inserm Emeritus Research Director at the Mediterranean Institute of Neurobiology (INMED), has made a breakthrough in the understanding of the disorder.

In an article published in Science, the researchers demonstrate that chloride levels are elevated in the neurons of mice used in an animal model of autism, and remain at abnormal levels from birth.

These results corroborate the success obtained with the diuretic treatment tested on autistic children by the researchers and clinicians in 2012, and suggest that administration of diuretics to mice before birth corrects the deficits in the offspring.

They also show that oxytocin, the birth hormone, brings about a decrease in chloride level during birth, which controls the expression of the autistic syndrome.

This work is due to appear in the 7 February 2014 issue of Science.

Neurons contain high levels of chloride throughout the entire embryonic phase. As a result, GABA, the main chemical messenger of the brain, excites the neurons during this phase instead of inhibiting them, in order to facilitate construction of the brain.

Subsequently, a natural reduction in chloride levels allows GABA to exercise its inhibitory role and regulate the activity of the adolescent/adult brain.

In many brain disorders (childhood epilepsy, cranial trauma, etc.), studies have shown abnormally high chloride levels.

Having made various observations, Dr Lemonnier's team (Brest), and Yehezkel Ben-Ari's team at Inserm carried out a clinical trial in 2012, based on the hypothesis of high chloride levels in the neurons of patients with autism.

The researchers showed that administration of a diuretic to children with autism (which reduces neuronal chloride levels) has beneficial effects.

The results of the trial supported this hypothesis, but because high neuronal chloride levels could not be demonstrated in children with autism, it was not possible to prove the mechanism proposed or justify the treatment.

In the present study, the researchers therefore used two animal models of autism, a genetic model, Fragile X syndrome, which is the genetic mutation most frequently associated with autism, and another, generated by injecting the pregnant mice with sodium valproate, a product known to generate abnormalities in children, including autistic spectrum disorder.

A high level of chloride in the brain
For the first time, the researchers recorded the activity of neurons at the embryonic stage and immediately after birth to observe modifications in chloride levels.

These observations showed that neuronal chloride levels are abnormally high in both young and adult animals used in the autism model.

GABA strongly excites neurons, and the researchers recorded aberrant electrical activities in the brain, which persist in adult animals.

The fall in chloride level, a particularly impressive phenomenon seen at birth in control animals, is absent in both of these animal models, and the neurons have the same chloride level before and after birth.

These high levels are due to reduced activity of a chloride transporter, thus preventing transport of chloride out of the neuron. As a result, a major feature of neurons during birth is abolished in animal models of autism.

Clinical trials of the drug bumetanide administered in young children with autistic symptoms are showing progress. 

Credit: D.C. Ferrari

"Chloride levels during delivery are determinants of the occurrence of autism spectrum disorder," explains Yehezkel Ben-Ari, an Emeritus Research Director at Inserm.

Beneficial effects of the diuretic on brain activity.
The researchers administered a diuretic treatment to the mother (in both animal models) for 24 hours shortly before delivery to see if this would restore brain inhibition in the offspring.

They showed that the drop in chloride level was re-established in the neurons several weeks after a single treatment during birth.

According to the research team, antenatal treatment restored brain activity to approximately normal levels, and corrected the "autistic" behaviour in the animals once they became adults.

"These results thus validate the working hypothesis that led us to the treatment we developed in 2012," states the principal author of the study.

Oxytocin, the birth hormone, naturally reduces chloride levels
The role of oxytocin in reducing neuronal chloride was also studied. The researchers had previously shown in 2006 that this hormone, which triggers labour, also has many beneficial actions on the brains of newborns, including protective effects in the event of complications during delivery, and even analgesic properties.

Oxytocin acts like the diuretic, reducing the intracellular chloride levels.

By administering the drug bumetanide to pregnant mice with models of autism, the researchers were able to reduce chloride levels in the brains of their offspring to their appropriate levels -- and in turn, to restore the GABA switch mechanism required for healthy brain development. 

Credit: D.C. Ferrari

In the present study, the team tested the long-term effects of blocking the actions of the hormone before birth.

A drug that blocks the signals generated by oxytocin was injected into pregnant mice.

The researchers evaluated the effects of this blockage on the offspring, and showed that it reproduced the entire autism-like syndrome in them, both with respect to the electrical and behavioural aspects (identical to the two animal models of autism).

As a result, the hormone's natural actions, just like those of the diuretic, are crucial to this delicate phase, and may control the pathogenesis of autism via the cellular chloride levels.

"These data validate our treatment strategy, and suggest that oxytocin, by acting on the chloride levels during delivery modulates/controls the expression of autism spectrum disorder," states Yehezkel Ben-Ari.

Taken together, these observations suggest that earliest possible treatment is essential for maximum possible prevention of the disorder.

This work raises the importance of carrying out early epidemiological studies in order to better understand the pathogenesis of the disorder, especially through analysing data on deliveries where a drop in chloride has occurred.

Indeed, complicated deliveries with episodes of prolonged lack of oxygen, for example, or complications during pregnancy, such as viral infections, are often suggested as risk factors.

Finally, given the role of oxytocin in triggering labour, "although it is true that epidemiological data suggesting that scheduled caesarean deliveries may have increased the incidence of autism are controversial, it nonetheless remains that these studies should be followed up and extended to confirm or refute this relationship, which is still possible," insists Yehezkel Ben-Ari, who concludes,

"To treat this type of disorder, it is necessary to understand how the brain develops and how genetic mutations and environmental insults modulate brain activity in utero."

More information: : "Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring," by R. Tyzio et al. Science, 2014. DOI: 10.1126/science.1247190

Autism, ADHD and Dyslexia: Can Animals rescue children

For years, studies have demonstrated the capacity of animals in encouraging social interaction among humans.

People walking a dog are more likely to receive positive social approaches than those walking alone.

Animals have been used in preschool and elementary school settings to serve as a social opportunity for children with and without disabilities.

Animals can also help children with learning and behavioural issues?

A family dog helps the development of a child
Pet therapy was first used by psychiatrist Boris Levison in 1953 – who used a dog to work with autistic children.

Dr. Levinson found the dog provided the child the opportunity to experience internal and external sensations – something the child could not do with people.

"A pet is an island of sanity in what appears to be an insane world. Friendship retains its traditional values and securities in one's relationship with one's pet. Whether a dog, cat, bird, fish, turtle, or what have you, one can rely upon the fact that one's pet will always remain a faithful, intimate, non-competitive friend -- regardless of the good or ill fortune life brings us." - Dr. Boris Levinson, child psychologist

The movie called “After Thomas” popularised the notion of using pets – particularly dogs for children with autism.

The boy in the movie (and in real life) only spoke in repetitive echolalic style sentences and was beyond the reach of his parents. His grandmother suggested the family adopt a dog.

The child flourished as a result of his bond with their pet dog. He is now described as a confident, friendly teenager who plays guitar in a band and also does volunteer work.

Bringing animals into a home of a child with ASD has been related to increased empathy and pro-social behaviour.

Service Dogs
Having a service dog in the home helps the ASD child by improving their mood and sense of well-being.

A published study in PLOS ONE , on February 27, 2013, and another study reported in SAGE compared social interaction between neuro-typical children and children with ASD in the presence of an animal or toys.

Researchers reported that children with ASD showed more social approach behaviors such as talking, looking at faces and making tactile contact as well as received more social approaches from their peers when an animal was present rather than if toys were present.

They also displayed less self-focused behaviours such as crying and whining and more pro-social behaviors such as smiling behaviors when the animals were present.

Therapeutic Riding (hippotherapy) has also shown benefits in children with autism. One study showed a significant decrease in childhood autism rate scale (CARS) after 3-6 months of riding.

Another study showed that therapeutic riding helped with sensory integration, directed attention and improved social motivation while decreasing inattention and distractibility.

In a new study, in the Journal of Autism and Developmental Disorders, researchers found that children who participated in therapeutic riding improved their abilities to relate appropriately to people, events or objects; translating into better relationships with classmates.

Also noted were improvement in sensory tolerance and less prompting to participate in school lessons.

Riding horses can help children with ADHD
Researchers at Arizona State University found that children with ADHD who rode horses demonstrated significantly greater improvements in reaction time, movement time, self-esteem, reduced depression, and decreased anxiety when compared to non-riders.

Horses have also provided a unique setting for group ADHD therapy that requires children to interact with one another in order to help the horse through a given scenario.

For instance, if the children are helping the horse through an obstacle course, they need to communicate with one another, be supportive, and handle their emotions.

Parents involved in a study to see if dogs can help with their children’s behavior have also been seeing positive effects.

Researchers and parents are stating their children are calmer which helps them function better at school and do better in subjects and they are also noting improved social skills.

Dogs help children with autism feel more comfortable

Children with dyslexia or difficulty reading are often hesitant to read aloud for fear of being judged and feeling embarrassed but these same children often times feel at ease around a dog who is there just to listen to the story – not to critique their reading abilities.

Reference

• Does Pet Arrival Trigger Prosocial Behaviors in Individuals with Autism? 
• Sentinels of Safety: Service Dogs Ensure Safety and Enhance Freedom and Well-Being for Families With Autistic Children
• Social Behaviors Increase in Children with Autism in the Presence of Animals Compared to Toys
• Prospective trial of equine-assisted activities in autism spectrum disorder.
• Kenro Dog Training

Author of Book on Autism and Animals Responds to New Pet Study

A study released today indicates that the addition of a pet to the household may help autistic children develop skills.

This empirical research backs up what many working in the field of human-animal interactions have known for a long time.

For some children with autism, interacting with companion, therapy, or service animals can be life-changing.

Merope Pavlides, author of “Animal-assisted Interventions for Individuals with Autism,” urges families to think carefully, however, about how to best involve animals in their childs life.

Sometimes a study like this can drive families to act hastily, Pavlides notes. Adding a petno matter what the speciesshould be done thoughtfully, with careful consideration to the needs of the whole family. Pavlides, a special educator and dog trainer, has worked with many special needs families.

She recently conducted a webinar through the Association of Pet Dog Trainers to help dog trainers work more effectively with autistic children, and will be writing a series of articles for “The Chronicle of the Dog” on this topic.

People who work with autistic kids and animals often see amazing progress in their clients, Pavlides says.

For some childrenand adultson the autism spectrum, engaging with an animal can open up channels of communication and interaction that were previously closed.

That said, not all autistic people are going to find animal interactions helpful or even pleasant. For some, sensory issues triggered by proximity to animals can be overwhelming.

How can you tell if getting a pet for your child is the right choice? There are lots of ways to test out your childs responsiveness to animals, Pavlides says.

Many therapy animal groups provide opportunities for children with disabilities to interact with pets.

Consider how your child responds to pets he or she comes into contact with in the family or neighborhood.

The Horse Boy Trailer - Working with Autism using animals

The Horse Boy does more than chronicle Rowan and his parents' journey across the vast, wild landscape of Mongolia. It delves into the strange world of autism itself, the relationship between humans and animals and between different cultures and different ways of being (autistic vs. normal, or "neuro-typical"), and the nature of healing. But above all, The Horse Boy tells the story of a couple that goes to the end of the earth to find a way into their son's life.

Gillian Naysmith has been asked by Author/Director, Rupert Isaacson to screen his movie 'The Horse Boy' about his Autistic Son, Rowan and his incredible relationship with horses and the families amazing adventure, as a fundraising event to raise funds for his new charity The Horse Boy Foundation UK.

This charity will help fund places for families of Autistic children to attend Horse Boy Camps throughout the UK. Gillian went to the Scottish camp in January and says it was incredible. Details of her son's progress can be found on the news page the website - www.gilliannaysmith.com

Tickets to the film being shown at Bells Distillery, Pitlochry in Scotland on Wednesday 4th August at 7pm are £5.50 and are available by contacting Gillian on - horseboy@gilliannaysmith.com or call 07934628326.