Can inhibiting neural signalling help improve sensory processing?
Source here
Just like how we need brakes in our cars to be able to slow down when driving, we need gamma-aminobutyric acid (GABA) in our brains to slow down signal transmission.
GABA, an inhibitory neurotransmitter, inhibits neuronal firing by binding to GABA receptors on a neuron and decreasing the likelihood of that neuron firing action potentials. This inhibition is important for the proper functioning of neural circuits, similar to how car brakes are important for safe driving. Altered GABA signalling is implicated in various disorders such as mood disorders, autism spectrum disorder, epilepsy, and Huntington disease. Drugs that affect GABA signalling can be used to treat these disorders and are also often used as anesthetics, sedatives, and muscle relaxants.
One such drug that exerts its mechanism of action through GABA signalling is baclofen, a GABA receptor agonist, meaning that the drug binds to GABA receptors and activates them like the neurotransmitter itself would. Baclofen is currently prescribed for various conditions including muscle twitching, spasticity, hiccups, and alcohol withdrawal.
A recent study conducted by researchers at Western University found promising results for the usage of one of the formulations of baclofen, R-baclofen, for reducing unwanted changes in sensory processing. This research was conducted with Cntnap2 knock-out rats, which are rats that have a genetic mutation in the Cntnap2 gene. Previous studies have shown that Cntnap2 knock-out rats are more reactive to sound and have an impaired ability to filter sensory information compared with wildtype rats (i.e., rats that do not have the genetic mutation). These auditory processes are studied in rats by playing sounds through a speaker system and then measuring the rats’ reactions to those sounds using a motion-sensitive platform. In this study, the researchers injected wildtype rats and Cntnap2 knock-out rats with either saline or R-baclofen and observed how the drug treatment impacted the rats’ sensory processing.
The first component of sensory processing that the researchers investigated was the acoustic startle response. The acoustic startle response is an involuntary reaction in response to loud, sudden sounds. Louder sounds generally elicit larger startle responses, quantified as increased motion measured on the motion-sensitive platform. Cntnap2 knock-out rats have increased acoustic reactivity compared with wildtype rats, meaning that they respond more strongly to startling sounds than wildtype rats. In humans this would look like one person who jumps in response to a car horn honking (the “Cntnap2 knock-out”) versus another person who barely reacts to the car horn (the “wildtype”). The researchers found that R-baclofen injections decreased acoustic startle responses in both wildtype and Cntnap2 knock-out rats compared to rats that received saline injections. The startle responses in R-baclofen treated Cntnap2 knock-out rats were decreased to levels that were similar to untreated wildtype rats.
Next the researchers looked at sensorimotor gating, which is a process that “gates” out irrelevant sensory information to help prevent sensory overload. A well-known example of sensorimotor gating is the cocktail party effect, allowing you to focus on one person speaking even though there are many other voices talking around you. One way to assess sensorimotor gating in rats is through prepulse inhibition, which is when a quieter, non-startling sound is presented before a startling sound, and this decreases the startle response to the startling sound. Cntnap2 knock-out rats have decreased prepulse inhibition compared with wildtype rats, indicating that they have impaired sensorimotor gating capabilities. R-baclofen injections increased certain prepulse inhibition measures in Cntnap2 knock-out rats back to levels comparable to untreated wildtype rats.
Finally, the researchers investigated how R-baclofen treatment would impact sensory filtering, another process that helps to extract relevant information from irrelevant stimuli. Sensory filtering was measured through habituation experiments. Habituation is the process by which we get accustomed to a stimulus after repeated exposure to it, like how over time you get used to the sound of traffic or the hum of the AC running. Habituation can be assessed in rats by calculating how much their startle responses decline as the rats are repeatedly presented with loud sounds. Cntnap2 knock-out rats have decreased habituation scores compared with wildtype rats, which shows that they have impaired sensory filtering capabilities. R-baclofen injections increased habituation scores in both wildtype and Cntnap2 knock-out rats compared to saline injections.
Overall, this study showed that R-baclofen, a GABA receptor agonist, could be a potential drug treatment for helping with increased acoustic reactivity, deficits in sensorimotor gating, and deficits in sensory filtering. These sensory processes are relevant to many neurological disorders, such as acoustic hypersensitivity in autism spectrum disorder and disrupted prepulse inhibition and habituation in schizophrenia. Future studies could further investigate the properties of this drug and its potential application in treating disorders with altered sensory processing.
Original article: Möhrle, D., Wang, W., Whitehead, S. N., & Schmid, S. (2021). GABAB Receptor Agonist R-Baclofen Reverses Altered Auditory Reactivity and Filtering in the Cntnap2 Knock-Out Rat. Frontiers in integrative neuroscience, 15, 710593. https://doi.org/10.3389/fnint.2021.710593