How a genetic mutation can change the way you process sounds
Have you ever watched X-Men, or The Incredible Hulk, or even Teenage Mutant Ninja Turtles? The characters in these movies and shows all have genetic mutations that changed their bodies in some way, leading to their supernatural abilities. Similarly, in our world, evidence shows that specific genetic mutations are associated with differences in human behaviour and physiology. For example, proven causalities between genetic mutations and disorders include the CFTR gene and cystic fibrosis; chromosome 21 and Down syndrome; and BRCA1, BRCA2, and breast cancer. Mutations in genes can cause these bodily changes because genetic mutations may result in altered protein functions. Proteins are essential for cells to function properly. Changes in proteins thus can have a large impact on our cells, which could ultimately affect our organ function and can cause changes in our behaviour.
The CNTNAP2 gene has been found to be mutated in various disorders in humans, in particular autism spectrum disorder (ASD). It is important to note that there is no single cause for ASD. There are numerous environmental risk factors and genetic mutations that are associated with ASD, and CNTNAP2 is simply one of those risk genes. The protein product of the CNTNAP2 gene, CASPR2, is known to play an essential role in neurodevelopment and neuronal function.
ASD is characterized by impairments in communication and social interaction as well as restrictive, repetitive behaviours (e.g., repetitive body movements, ritualistic behaviours). Rats that have been genetically modified to have mutations in the Cntnap2 gene display characteristics that parallel these behaviours observed in autistic people. The Cntnap2 mutation in these rats leads to loss of function of the protein product, and so these rats are referred to as Cntnap2 knock-out rats. Notably, Cntnap2 knock-out rats exhibit altered sensory processing compared to rats without mutations in the Cntnap2 gene, referred to as wildtype rats. For example, Cntnap2 knock-out rats are more sensitive to sound, especially loud sounds. In humans, this would look like reacting to quiet sounds as if they were loud or being frightened by sounds that do not bother other people. Additionally, Cntnap2 knock-out rats have decreased sensory filtering, which is a process that helps to prevent sensory overload by filtering sensory information so that the brain can focus on more pertinent information.
Understanding the neural mechanisms underlying this altered sensory processing in Cntnap2 knock-out rats can allow us to widen our understanding of ASD. Complex neurodevelopmental disorders like ASD are poorly understood at the molecular level, which is why we currently have few treatments available. Research using animal models such as this one could help with developing treatments for altered sensory processing in ASD. Indeed, a recent study used Cntnap2 knock-out rats to test a drug, R-Baclofen, and observed that this drug helped improve sensory processing disruptions in Cntnap2 knock-out rats. Thus, studying Cntnap2 knock-out rats is beneficial for both understanding ASD itself and for studying possible treatments for ASD.
Research conducted by Dr. Kaela Scott and colleagues at the University of Western Ontario investigated the auditory cortex in Cntnap2 knock-out rats. The auditory cortex is responsible for perception of auditory information. In humans, the auditory cortex plays a role in identifying musical pitch, language comprehension, and determining where a sound is coming from. Similarly, in rats, the auditory cortex is responsible for the perception of vocalizations from other rats and how sound is perceived over time, which is also known as temporal processing. Scott and colleagues implanted electrodes in the auditory cortex to record activity from groups of neurons as a speaker played 50-ms, 90 dB sounds to activate these neurons in the auditory cortex. The researchers found that neurons in the auditory cortex of Cntnap2 knock-out rats are more responsive to sound as indicated by increased firing rates and longer response durations compared with wildtype rats.
The researchers also looked into temporal processing in Cntnap2 knock-out rats. They played short sound pulses, repeated six times in a row, presented at varying rates. Faster rates made it harder for neurons to respond to acoustic stimuli in both wildtype rats and Cntnap2 knock-out rats. However, this effect was exaggerated in Cntnap2 knock-out rats. Neurons in Cntnap2 knock-out rats had decreased firing rates compared with wildtype rats in response to sound pulses presented very rapidly. This decreased firing rate indicates that neurons in the auditory cortex in Cntnap2 knock-out rats have greater difficulty with processing auditory information from rapidly presented sounds.
Overall, this study showed that Cntnap2 knock-out rats have hyper-excitable neurons in the auditory cortex and that these neurons have altered auditory temporal processing, which may explain some of the sensory processing alterations that are caused by mutations in the Cntnap2 gene. This research is an important step towards understanding the neural changes that contribute to behavioural differences in CNTNAP2-associated neurological disorders in humans, such as ASD. Fundamental research such as this study is crucial to understanding the mechanisms underlying ASD and hopefully can lead to future studies in developing effective treatments.
Original article: Scott, K. E., Mann, R. S., Schormans, A. L., Schmid, S., & Allman, B. L. (2022). Hyperexcitable and Immature-Like Neuronal Activity in the Auditory Cortex of Adult Rats Lacking the Language-Linked CNTNAP2 Gene. Cerebral cortex (New York, N.Y. : 1991), bhab517. Advance online publication. https://doi.org/10.1093/cercor/bhab517