Altered Trajectory of Brain Development in Autism Spectrum Disorder
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The brain is an incredibly complex organ, and even slight disturbances in its development can change how we sense and interact with our environment, which can manifest as disorders. Autism spectrum disorder (ASD) is one such neurodevelopmental disorder, which is generally diagnosed early on in children and significantly affects everyday life. In Canadian children, the prevalence of ASD diagnosis is 1 in 50, with males 4 times more likely to be diagnosed than females.
To be diagnosed with ASD, changes in two major categories of behaviours must be seen: social behaviours, such as impaired verbal communication; and restricted and repetitive behaviours, such as repetitively listening to one song, or repetitive movements like rocking back and forth. Importantly, animals like mice and rats also exhibit these kinds of behaviours when DNA changes that lead to ASD in people are introduced in the animals, like the deletion of certain genes. These animals are called animal models of ASD, and they are used to closely study changes associated with ASD at microscopic levels, which would not be possible to study in humans.
A recent study from Western University used one such rat model of ASD to understand the changes that happen in the brain in ASD. This study used rats that had mutations in Cntnap2, which is a gene that was originally discovered to be mutated in a population of humans that exhibited the core symptoms of ASD. Specifically, this study looked at the brain areas responsible for processing sounds, since increased sensitivity to sounds is a very common symptom of ASD. Further, since ASD is a disorder that stems from issues in the early life development of the brain, changes were studied over three developmental timepoints, which were: a very young age (8-12 days old), an intermediate young age (18 to 21 days old), and adult age (70 to 90 days old).
The function of the brain essentially entails brain cells, called neurons, ‘talking’ to each other through electrical activity, which can be observed by researchers using several methods. This study used a technique called patch-clamp electrophysiology, which allows one to record electrical activity of individual neurons. Since these ASD model rats are more reactive to sounds throughout their lives, the researchers expected the deletion of Cntnap2 to alter the activity of neurons in the sound processing brain areas throughout development.
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The major changes in the brains of ASD model rats were seen during the intermediate young age (18-21 days old). During this young age, individual neurons in the ASD model rats had faster electrical activity and were more easily excitable compared to those in controls. These differences disappeared by the adult age. As these ASD model rats are more reactive to sounds, it is entirely possible that the increased excitability of these neurons contribute to the hyperreactivity. However, the ASD model rats remain hyperreactive to sounds throughout their lives, so the excitability of neurons cannot entirely explain this behaviour, as it normalizes by adulthood.
Neurons form connections with each other using ‘wires’, called dendrites and axons, and use these to receive and send electrical information between neurons and large networks of neurons. Importantly, these connections between neurons can change constantly depending on our experiences and environment. For example, connections between networks of neurons are formed when we learn something new, i.e. a new skill like sewing or a math equation. These connections are strengthened with repetitions of the task, which in turn helps us solidify the new skill or knowledge in our memory. If there were problems in the strengthening of these connections, the brain would not be able to retain these skills. Moreover, the strength and activity level of these connections tend to differ in brain-related disorders and diseases. In the study, the electrical activity between these connections was found to be weaker but more frequent in the ASD model rats compared to control rats at both young and adult ages.
During the young ages (particularly the intermediate young age in rats), a large amount of ‘remodeling’ takes place, and this time during development is called the ‘critical period’, where connections between neurons are made and lost on a large scale, depending on their usage. For example, infants are capable of learning all languages at a native speaking level, and brain connections will form for the languages that they are exposed to. However, after the critical period passes, the ability to quickly learn languages is not as easy because creating new connections between neurons becomes harder and the unused neurons are lost. Since connections between neurons are highly affected by their activity level, the increased excitability and activity of neurons during the young age in the ASD model rats likely caused alterations in the connections between neurons. The changes in the neuronal connections in the sound processing brain areas were evidently long-lasting, as they were seen in the adult ages as well. As these changes were observed in young and adult rats, they could underlie the increased reactivity to sounds that is observed throughout their lives.
The important takeaway of this study is that the largest differences in sound processing brain areas in the ASD model rats is during a young age that is considered a critical period of development, and the connections between neurons and networks established during this time persist into adulthood. A past study has shown that intervention during the critical period can alter the trajectory of development, and change the connections between neurons and their networks. The current study supports the idea that interventions during the critical period would likely be an effective way to change the trajectory of the development of neuronal connections, and therefore treat symptoms like hyperreactivity to sound. Ongoing studies are exploring treatments during the critical period, so stay tuned for future research!
References:
Scott KE, Schormans AL, Pacoli KY, De Oliveira C, Allman BL, Schmid S. Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders. J Neurosci. 2018 Oct 3;38(40):8588-8604. doi: 10.1523/JNEUROSCI.0759-18.2018.
He Q, Arroyo ED, Smukowski SN, Xu J, Piochon C, Savas JN, Portera-Cailliau C, Contractor A. Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. Mol Psychiatry. 2019 Nov;24(11):1732-1747. doi: 10.1038/s41380-018-0048-y.
Original article:
Mann RS, Allman BL, Schmid S. Developmental changes in electrophysiological properties of auditory cortical neurons in the Cntnap2 knockout rat. J Neurophysiol. 2023 Apr 1;129(4):937-947. doi: 10.1152/jn.00029.2022.