Background

Autism spectrum disorder (ASD) is estimated to affect about 1 in every 59 children.¹ Over the last few decades ASD research has focused on symptoms involving impaired social behaviors such as disrupted communication and stereotyped behaviors. However when it comes to motor skill dysfunctions commonly observed during childhood ASD, these are not well characterized or understood. In a study recently published in Nature Neuroscience, researchers investigated the neurological mechanisms behind these motor deficits. They found that a mice model with ASD-related gene variation caused impairments in cerebellum dependent motor learning that was associated with a shortage in the amount of the neurotransmitter noradrenaline released into the brain’s primary motor cortex. However after activation of the noradrenergic neurons in that brain region there was improvement in the delayed motor learning of the mice.² These results indicate a unique role of noradrenergic modulation in the delayed motor learning of autism and will pave the way for further research into the neural circuit dysfunctions associated with ASD. 

Autism is a developmental disorder characterized by challenges in social interaction and repetitive/restricted interests or behaviors.³ Children with ASD often experience delays in key motor developmental milestones such as crawling and speech articulation.⁴ Difficulties in motor development are typically not considered primary diagnostic tools for ASD, however researchers have shown increasing interest in the importance of distinguishing these motor differences in children with ASD to improve diagnosis and treatment.⁵ One common copy number variation associated with ASD is the 16p11.2 deletion, and more than 70% of carriers for this variation exhibit abnormal speech control and motor learning during childhood.² In this study this was investigated further using mice with a deletion of the chromosome 16p11.2 to see if they exhibit motor deficits similar to ASD. Neuromodulators within the brain also play a critical role in arousal, motivation and information processing.⁶  In the motor cortex, neuromodulators like dopamine (DA), acetylcholine (ACh) and noradrenaline (NA), have been shown to regulate plasticity and cortical organization during motor learning, and dysfunctions of these systems have been observed in ASD.⁶ Researchers also sought to determine whether these neuromodulatory transmitter systems are impaired in 16p11.2+/− mice. 

Methods

In this study done by Yin et al., the researchers used a mouse model of autism to demonstrate effects of decreased noradrenaline release into the brain’s primary motor cortex. They identified motor deficits originating in the locus coeruleus which is an area of the hindbrain that functions in motivation, alertness, and attention. ² First, they used an accelerating rotarod test and trained both wild-type (WT) and 16p11.2+/− mice for ten consecutive sessions. They then used a separate head-fixed motor learning task. In this task, mice were trained to run on a bidirectional rotating-disk with their head fixed. The body movements of the mice were tracked in order to quantify behaviorally relevant movement dynamics, because reduction in motor movement variability is closely linked to motor learning. ⁷  To examine whether learning-induced spine reorganization is altered in the 16p11.2+/− mice, they performed imaging and observed dendritic spine changes at different points during training and at baseline. To examine the effect of noradrenergic activity in the motor cortex, while training, either saline or a norepinephrine receptor antagonist cocktail was injected into the motor cortex. 

Results

After training both groups during the first task, the learning rate in the 16p11.2+/− mice was significantly slower before reaching a performance level similar to WT mice, indicating a delay in motor learning.² In the second task, during the first training session, both WT and 16p11.2+/− mice showed similar movement attempts and were not able to smoothly control the rotation of the bidirectional disk under head-fixation. However, WT mice learned to adjust their body to run smoothly on the rotating disk, while the 16p11.2+/− mice showed a slower rate of improvement. Overall the behavioral results from both tasks demonstrated that the autism model mice did not exhibit gross movement deficits, but required a longer training process to acquire new motor abilities. After imaging analysis, they found that the brains of ASD mimic mice showed a delay in removing old substrates while forming new ones. Spine elimination that normally happens following spine formation was delayed in the 16p11.2+/− mice. Researchers attributed this to be caused by an effect called “low signal-to-noise ratio”, where old established memories are considered to be “noise”, creating confusion in the brain. Pharmacogenetic activation of locus coeruleus noradrenergic neurons was found to improve the circuit deficits, delayed motor learning, and spine reorganization delay in these mice.²

Children with ASD tend to show a delay in motor learning which is normally overlooked and attributed to social deficits. However these results indicate there may be more to the story. These children could be learning at a slower pace, contributing to their social interactions and impacting their everyday lives. The 16p11.2-deletion mice motor skills improved quicker by increasing noradrenaline in the motor cortex, and may contribute to further research into using noradrenaline for treatments to help patients learn motor skills at a faster pace. This study provides a good foundation for discovering the many factors at play in motor skill ASD symptoms, however further research needs to be done into the different neuromodulatory systems that play a role in ASD. This will aid in the development of improved therapeutic strategies for counteracting the neural circuit dysfunctions commonly associated with ASD.

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