Researcher identified the molecular aberrations that give rise to heightened touch sensitivity in autism spectrum disorders


The inability to tolerate light touch is a telltale feature of autism and one of the disorder’s many perplexing symptoms. It has defied treatment, and its precise origins have remained somewhat of a mystery.

Now a study led by investigators at Harvard Medical School’s Blavatnik Institute has not only identified the molecular aberrations that give rise to heightened touch sensitivity in autism spectrum disorders but also points to a possible treatment for the condition.

The research, conducted in mice and published Aug. 8 in Cell, shows that an old experimental compound that exclusively targets the peripheral nerve cells not only mitigated abnormal touch sensitivity, but also improved body mass, alleviated anxiety and, in a subset of mice, prevented the development of certain brain abnormalities that arise from altered touch response.

If affirmed in further studies, the findings could help pave the way toward much-needed treatments, the research team said.

Current therapies, while somewhat effective, remain suboptimal because they cross the blood-brain barrier and cause sedation and memory problems.

“More and more people are diagnosed with autism and related disorders and the need to identify effective therapies with minimal or no side effects is acute.

We believe our findings set the stage for the development of a new class of medicines that may not only treat sensory overreactivity but some of the other core behaviors seen in autism spectrum disorders,” said study senior investigator David Ginty, professor of neurobiology in the Blavatnik Institute at Harvard Medical School and a Howard Hughes Medical Institute investigator.

Additionally, the findings underscore just how important the peripheral nervous system is to brain development, the team said, providing a key clue into now-classic observations that young children deprived of normal touch during infancy have a greater risk of behavioral abnormalities in later life.

“Our findings help provide a molecular basis for a phenomenon that physicians and scientists have observed for decades,” said study first author Lauren Orefice, assistant professor of genetics in the Blavatnik Institute at Harvard Medical School and the Department of Molecular Biology at Massachusetts General Hospital.

“Our results add to a growing body of evidence demonstrating that abnormalities in peripheral neurons can hamper the development of key areas of the brain in newborn animals and contribute to behavioral problems later in life.”

Earlier work by the same team identified defects in two specific genes – Mecp2 and Gabrb3 – as the underlying drivers of abnormal touch sensitivity.

Their absence in peripheral neurons, the work showed, decreases the activity of a key neurotransmitter, GABA, a chemical known to tamp down nerve signaling and regulate nerve-to-nerve communication in the spinal cord and brain.

These findings also showed that low GABA-receptor activity in peripheral sensory neurons underlies aberrant neuronal signaling and overactive nerve-cell firing in the spinal cords of mice lacking Mecp2 or Gabrb3, thus leading to heightened touch sensitivity.

Building on these findings, Ginty, Orefice and colleagues conducted a series of experiments demonstrating that each of these, as well as other genes linked to autism spectrum disorders, regulate distinct properties of peripheral neurons. When absent or defective, they give rise to altered sensitivity to light touch.

The new study additionally demonstrates that mice lacking yet another gene, Shank3, also had abnormal touch responses. However, the malfunction in neurons lacking Shank3 was different from the dysfunction seen in neurons lacking the other two genes, the study showed. Shank3-deficient neurons retained normal GABA signaling but had altered function in these cells’ potassium channels, which rendered them more excitable. Animals whose peripheral neurons lacked Shank3 also exhibited traits associated with autism, including anxiety and social impairment.

Next, the researchers examined the interplay between peripheral neuronal genes and the central nervous system.

They turned their attention to key areas in the brain that receive and process touch signals from the peripheral nerves.

The experiments revealed that animals lacking Mecp2, Gabrb3 and Shank3 genes only in their peripheral neurons had marked alterations in brain circuits that regulate and process touch sensation.

Conversely, restoring the presence of these genes in the peripheral neurons improved circuit development and function in the brains of newborn mice and restored normal touch sensitivity—an observation that underscores the critical role that peripheral nerve activity plays in brain development, the researchers said.

Notably, the scientists observed that mice that showed the most serious alterations in brain development and exhibited the most serious symptoms were the animals in whom gene mutations had occurred early in development.

The finding, the team said, highlights the critical importance of normal peripheral nerve function early in life to ensure proper brain development.

Given that alterations in Mecp2 and Gabrb3 genes cause abnormal touch sensitivity and impact brain development by modulating signaling by the neurotransmitter GABA, the researchers decided to test whether increasing GABA-receptor activity would reduce the aberrant neuronal firing and normalize touch sensitivity. Indeed, boosting GABA activity nearly normalized the animals’ response to touch.

One of the central challenges in treating touch hypersensitivity stems from the fact that current GABA-modulating drugs sometimes used to treat the condition cross the blood-brain barrier and cause sedation and, at times, cognitive problems. The researchers needed a way to precision-target peripheral nerves without affecting the brain.

They turned to isoguvacine, an experimental compound from the 1970s that activates GABA receptors but is believed to be incapable of permeating the blood-brain barrier.

“Years ago, we started thinking ‘Wouldn’t it be lovely to be able to harness the power of these GABA drugs but restrict their activity to peripheral nerves?” Ginty said.

They were able to do precisely that.

Indeed, a series of experiments showed that treatment with isoguvacine normalized touch sensitivity in animals with features of autism-spectrum disorders and even attenuated anxiety and abnormalities in certain social behaviors.

The results, the researchers said, could help set the stage for developing treatments that recapitulate the drug’s effects.

“What we would like to see happen is the development of a new class of compounds that are chemically altered to act selectively on peripheral nerves while sparing the brain,” Ginty said. “That’s the simple dream we’ve had, and our findings bring it just a bit closer within reach.”

Children and adults with autism, as well as those with other developmental disabilities, may have a dysfunctional sensory system – refered to as sensory integration disorders in ASD. Sometimes one or more senses are either over- or under-reactive to stimulation.

Such sensory problems may be the underlying reason for such behaviors as rocking, spinning, and hand-flapping.

Although the receptors for the senses are located in the peripheral nervous system (which includes everything but the brain and spinal cord), it is believed that the problem stems from neurological dysfunction in the central nervous system–the brain.

As described by individuals with autism, sensory integration techniques, such as pressure-touch can facilitate attention and awareness, and reduce overall arousal.

Temple Grandin, in her descriptive book, Emergence: Labeled Autistic, relates the distress and relief of her sensory experiences.

Sensory Integration

Sensory integration is an innate neurobiological process and refers to the integration and interpretation of sensory stimulation from the environment by the brain.

In contrast, sensory integrative dysfunction is a disorder in which sensory input is not integrated or organized appropriately in the brain and may produce varying degrees of problems in development, information processing, and behavior.

A general theory of sensory integration and treatment has been developed by Dr. A. Jean Ayres from studies in the neurosciences and those pertaining to physical development and neuromuscular function.

This theory is presented in this paper. Evidence-based treatments for supporting people experiencing sensory differences can improve comfort and quality of life.

Sensory integration focuses primarily on three basic senses–tactile, vestibular, and proprioceptive.

Their interconnections start forming before birth and continue to develop as the person matures and interacts with his/her environment.

The three senses are not only interconnected but are also connected with other systems in the brain. Although these three sensory systems are less familiar than vision and audition, they are critical to our basic survival.

The inter-relationship among these three senses is complex. Basically, they allow us to experience, interpret, and respond to different stimuli in our environment. The three sensory systems will be discussed below.

Tactile System

The tactile system includes nerves under the skin’s surface that send information to the brain. This information includes light touch, pain, temperature, and pressure.

These play an important role in perceiving the environment as well as protective reactions for survival.

Dysfunction in the tactile system can be seen in withdrawing when being touched, refusing to eat certain ‘textured’ foods and/or to wear certain types of clothing, complaining about having one’s hair or face washed, avoiding getting one’s hands dirty (i.e., glue, sand, mud, finger-paint), and using one’s fingertips rather than whole hands to manipulate objects.

A dysfunctional tactile system may lead to a misperception of touch and/or pain (hyper- or hyposensitive) and may lead to self-imposed isolation, general irritability, distractibility, and hyperactivity.

Tactile defensiveness is a condition in which an individual is extremely sensitive to light touch.

Theoretically, when the tactile system is immature and working improperly, abnormal neural signals are sent to the cortex in the brain which can interfere with other brain processes.

This, in turn, causes the brain to be overly stimulated and may lead to excessive brain activity, which can neither be turned off nor organized. This type of over-stimulation in the brain can make it difficult for an individual to organize one’s behavior and concentrate and may lead to a negative emotional response to touch sensations.

Vestibular System

The vestibular system refers to structures within the inner ear (the semi-circular canals) that detect movement and changes in the position of the head.

For example, the vestibular system tells you when your head is upright or tilted (even with your eyes closed). Dysfunction within this system may manifest itself in two different ways. Some children may be hypersensitive to vestibular stimulation and have fearful reactions to ordinary movement activities (e.g., swings, slides, ramps, inclines).

They may also have trouble learning to climb or descend stairs or hills; and they may be apprehensive walking or crawling on uneven or unstable surfaces. As a result, they seem fearful in space. In general, these children appear clumsy. On the other extreme, the child may actively seek very intense sensory experiences such as excessive body whirling, jumping, and/or spinning. This type of child demonstrates signs of a hypo-reactive vestibular system; that is, they are trying continuously to sti mulate their vestibular systems.

Proprioceptive System

The proprioceptive system refers to components of muscles, joints, and tendons that provide a person with a subconscious awareness of body position.

When proprioception is functioning efficiently, an individual’s body position is automatically adjusted in different situations; for example, the proprioceptive system is responsible for providing the body with the necessary signals to allow us to sit properly in a chair and to step off a curb smoothly.

It also allows us to manipulate objects using fine motor movements, such as writing with a pencil, using a spoon to drink soup, and buttoning one’s shirt.

Some common signs of proprioceptive dysfunction are clumsiness, a tendency to fall, a lack of awareness of body position in space, odd body posturing, minimal crawling when young, difficulty manipulating small objects (buttons, snaps), eating in a sloppy manner, and resistance to new motor movement activities.

Another dimension of proprioception is praxis or motor planning.

This is the ability to plan and execute different motor tasks. In order for this system to work properly, it must rely on obtaining accurate information from the sensory systems and then organizing and interpreting this information efficiently and effectively.


In general, dysfunction within these three systems manifests itself in many ways. A child may be over- or under-responsive to sensory input; activity level may be either unusually high or unusually low; a child may be in constant motion or fatigue easily. In addition, some children may fluctuate between these extremes.

Gross and/or fine motor coordination problems are also common when these three systems are dysfunctional and may result in speech/language delays and in academic under-achievement. Behaviorally, the child may become impulsive, easily distractible, and show a general lack of planning. Some children may also have difficulty adjusting to new situations and may react with frustration, aggression, or withdrawal.

Evaluation and treatment of basic sensory integrative processes is performed by occupational therapists and/or physical therapists. The therapist’s general goals are: (1) to provide the child with sensory information which helps organize the central nervous system, (2) to assist the child in inhibiting and/or modulating sensory information, and (3) to assist the child in processing a more organized response to sensory stimuli.

Journal information: Cell
Provided by Harvard Medical School


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.