Introduction
Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions that affect how people communicate and interact with others. One of the common features of ASDs is sensory processing dysfunction, which means having abnormal responses to sensory stimuli such as sounds, lights, or touch. In fact, more than half of the people with ASDs report having difficulties with touch sensitivity, which can affect their social and emotional development.
But how does touch sensitivity relate to other autism behaviors, and when does it start to appear? A new study published in Nature Neuroscience in 2024 sheds some light on these questions by using mouse models of ASDs. The researchers found that different mouse models of ASDs show different patterns of touch sensitivity during development, and that these patterns can predict the emergence and severity of other autism behaviors later in life.
The mouse models of ASDs
The researchers used four different mouse models of ASDs, each with a genetic mutation that affects a different part of the somatosensory system, which is responsible for processing touch information. The four mouse models were:
- Mecp2 mice, which have a mutation in the Mecp2 gene that causes Rett syndrome, a severe form of ASD that affects mostly girls.
- Foxp1 mice, which have a mutation in the Foxp1 gene that affects the development of the cerebral cortex, the outer layer of the brain that is involved in higher cognitive functions.
- Mecp2;Foxp1 mice, which have both mutations and show more severe autism behaviors than either of the single mutants.
- Gabra3 mice, which have a mutation in the Gabra3 gene that affects the function of GABA, a neurotransmitter that inhibits neural activity.
The researchers also used wild-type mice, which have no mutations and serve as a normal control group.
The touch sensitivity tests
The researchers measured the touch sensitivity of the mice using two different tests:
- The von Frey test, which involves applying different forces of touch to the hind paw of the mouse and recording the withdrawal response. This test measures the threshold of touch perception, or how much force is needed to elicit a response.
- The air puff test, which involves delivering a brief puff of air to the whiskers of the mouse and recording the head movement response. This test measures the reactivity to touch, or how strongly the mouse reacts to a given stimulus.
The researchers performed these tests at different stages of development, from embryonic to adult, to track the changes in touch sensitivity over time.
The results
The researchers found that the four mouse models of ASDs showed different patterns of touch sensitivity during development, and that these patterns were related to the locus of the genetic mutation, or the part of the somatosensory system that was affected.
- The Mecp2 and Mecp2;Foxp1 mice, which have mutations that affect the feedback or presynaptic inhibition of the peripheral mechanosensory neurons, the nerve cells that detect touch stimuli, showed increased touch sensitivity from embryonic to adult stages. These mice had lower thresholds and higher reactivity to touch than the wild-type mice, meaning that they felt touch more intensely and reacted more strongly to it.
- The Foxp1 and Gabra3 mice, which have mutations that affect the feedforward or postsynaptic inhibition of the spinal cord, the part of the central nervous system that relays touch information to the brain, showed normal touch sensitivity at embryonic and neonatal stages, but increased touch sensitivity at juvenile and adult stages. These mice had similar thresholds and reactivity to touch as the wild-type mice at early stages, but developed lower thresholds and higher reactivity to touch later in life.
The researchers also found that the developmental timing of touch sensitivity was associated with the manifestation of other autism behaviors in adulthood, such as anxiety-like behaviors and social interaction deficits.
- The Mecp2 and Mecp2;Foxp1 mice, which showed early onset of touch sensitivity, also showed increased anxiety-like behaviors and reduced social interaction in adulthood. These mice spent more time in the dark and less time in the light in a light-dark box test, and showed less preference for a social partner over an object in a three-chamber test, compared to the wild-type mice.
- The Foxp1 and Gabra3 mice, which showed late onset of touch sensitivity, did not show any significant differences in anxiety-like behaviors and social interaction in adulthood compared to the wild-type mice. These mice spent similar amounts of time in the light and dark, and showed similar preferences for a social partner over an object, as the wild-type mice.
The implications
The study reveals that the developmental timing of touch sensitivity can predict the emergence and severity of other autism behaviors in mouse models, and that the locus of the genetic mutation dictates the timing of touch sensitivity. The study suggests that different mechanisms of sensory processing dysfunction may underlie the heterogeneity of ASDs, and that early interventions targeting touch sensitivity may help prevent or reduce the negative impact of ASDs on social and emotional development.
Faq
What are the advantages of using mouse models of ASDs?
Mouse models of ASDs are useful tools to study the genetic and neural mechanisms of ASDs, as they allow for precise manipulation and measurement of specific genes and circuits that are implicated in ASDs. Mouse models also enable longitudinal and cross-sectional studies of ASD-associated behaviors across different developmental stages.
What are the similarities and differences between the mouse models of ASDs and the human cases of ASDs?
The mouse models of ASDs and the human cases of ASDs have some similarities and differences. Some of the similarities are:
- Both mouse models and human cases of ASDs are caused by genetic mutations that affect the development and function of the nervous system, especially the somatosensory system.
- Both mouse models and human cases of ASDs show altered touch sensitivity and reactivity, as well as other ASD-associated behaviors, such as anxiety-like behaviors and social interaction deficits.
- Both mouse models and human cases of ASDs show heterogeneity and diversity in the phenotypic presentation and manifestation of ASDs, depending on the locus and timing of the genetic mutation and the circuit disruption.
Some of the differences are:
- Mouse models of ASDs are artificially created by manipulating specific genes and circuits that are implicated in ASDs, while human cases of ASDs are naturally occurring and influenced by various genetic and environmental factors.
- Mouse models of ASDs are limited in their ability to capture the full spectrum and complexity of ASDs, as they only measure certain aspects of ASD-associated behaviors, such as touch sensitivity, anxiety-like behaviors, and social interaction deficits, while human cases of ASDs involve other impairments in communication, cognition, and motor skills.
- Mouse models of ASDs are restricted to the somatosensory system, while human cases of ASDs involve other sensory and brain systems that are also affected by ASDs, such as the auditory, visual, and olfactory systems.
What are the differences between touch perception and touch reactivity?
Touch perception is the ability to sense and discriminate touch stimuli, such as the location, intensity, duration, and frequency of the stimuli. Touch reactivity is the ability to respond and adapt to touch stimuli, such as the withdrawal, habituation, or sensitization of the response. Touch perception and touch reactivity are both aspects of touch processing, but they are not the same. Touch perception is more related to the sensory and cognitive aspects of touch processing, while touch reactivity is more related to the motor and affective aspects of touch processing. Touch perception and touch reactivity may also have different neural mechanisms and correlates, such as the feedback and feedforward inhibition in the somatosensory system.
What are the potential mechanisms of tactile over-reactivity in the mouse models of ASDs?
The potential mechanisms of tactile over-reactivity in the mouse models of ASDs are related to the disruption of feedback or feedforward inhibition in the somatosensory system. Feedback inhibition is the inhibition that occurs when the output of a neuron or a circuit inhibits its own input, creating a negative feedback loop. Feedforward inhibition is the inhibition that occurs when the input of a neuron or a circuit inhibits its output, creating a positive feedback loop. Both types of inhibition are important for regulating the activity and sensitivity of the somatosensory system. In the Mecp2 and Mecp2;Foxp1 mice, the mutation in the Mecp2 gene impairs the feedback inhibition of the peripheral mechanosensory neurons, leading to increased release of neurotransmitters and enhanced excitability of the somatosensory system. In the Foxp1 and Gabra3 mice, the mutation in the Foxp1 or Gabra3 gene impairs the feedforward inhibition of the spinal cord interneurons, leading to reduced expression or function of GABA receptors and reduced inhibition of the somatosensory system.
What are the differences between anxiety-like behaviors and social interaction deficits in ASDs?
Anxiety-like behaviors are behaviors that indicate fear, stress, or nervousness in response to certain situations or stimuli. Social interaction deficits are behaviors that indicate impaired or reduced ability or interest in communicating and interacting with others. Anxiety-like behaviors and social interaction deficits are both common and core features of ASDs, but they are not the same. Anxiety-like behaviors are more related to the emotional and affective aspects of ASDs, while social interaction deficits are more related to the social and cognitive aspects of ASDs. Anxiety-like behaviors and social interaction deficits may also have different causes and correlates in ASDs, such as sensory processing dysfunction, genetic factors, or environmental factors.
How did the researchers measure anxiety-like behaviors and social interaction deficits in the mice?
The researchers used two behavioral tests to measure anxiety-like behaviors and social interaction deficits in the mice:
- The light-dark box test, which involves placing the mouse in a box that has a light and a dark compartment, and measuring the time spent in each compartment. Mice that spend more time in the dark compartment are considered to have higher anxiety-like behaviors.
- The three-chamber test, which involves placing the mouse in a box that has three chambers, one with an empty cage, one with a social partner (another mouse), and one with an object (a toy). The mouse is allowed to explore the box and the time spent in each chamber is recorded. Mice that show less preference for the social partner over the object are considered to have lower social interaction.
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