Disagreement in Research Regarding Cortical Hyperactivity in Children with Fragile X Syndrome and Autism Spectrum Disorder

Autism Spectrum disorder affects an estimated 1 in 100 children, and it is thought that both genetic and environmental factors play a role in developing ASD (World Health Organization, 2023). Fragile X Syndrome (FXS) is the most known cause of an inherited single-gene disorder, accounting for 1-6% of all ASD cases. Additionally, around 45% of males and 16% of females with FXS have ASD (CDC, 2022; Kaufmann et al., 2017). Given its prevalence and link with FXS, studying the most known cause of ASD by using the FXS population is important for further understanding the intricacies of its causes that can give further insight towards more effective treatment methods.

In 2022, Dr. Maggie Guy and colleagues performed a study entitled, “Cortical Source Analysis of the Face Sensitive N290 ERP Component in Infants at High Risk for Autism,” where they investigated appropriate head models for cortical source analysis in children with FXS, infant siblings of children with autism, and low risk controls to analyze the neutral mechanism of the face-sensitive N290 event-related potential (ERP). In this study, all children had greater N290 responses to faces compared to toys. However, there was a significantly greater N290 amplitude in response to familiar stimuli and more widespread activation in response to faces in children with FXS compared to the other two groups. This suggests that those with FXS demonstrate a hyperactivity due to the enhanced N290 and ERP responses.

Interestingly, the results of the recent study, “Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome,” from a team at the Université de Montréal lead by Roberto Araya and Diana E. Michell challenge the hyperactivity of FXS in Guy et al.’s study (Michell et al., 2023). The researchers described the crucial implications of this study in an interview with News Medical Life Sciences, explaining that they looked at the functioning of individual pyramidal neurons in cortical layer 5 associated with information output since sensory signals are integrated differently in those with ASD (Henderson, 2023). They found that unlike the previous work showing a hyperexcitable cortex, “the integration of sensory signals in cortical neurons is underrepresented in a murine [mouse] model of FXS” (Henderson, 2023). They used a tree analogy to explain the altered functioning of pyramidal neurons: the neurons of the tree are the branches, and the leaves are the dendrites. In the tree of someone with FXS, they propose that the areas around where the leaves project acting as “excitatory synapses” are blurred. This blurriness represents the distorted integration of sensory information one with FXS experiences.

They say that the protein FMRP that modules a potassium channel in the brain is absent in people with FXS. When this protein is absent, it impacts the way sensory inputs are combined, which is responsible for the lack of sensory signals coming from the cortical pyramidal neurons. Therefore, this study provides a new strategy that shows they can restore cortical neurons without the FMRP protein. Having the ability to do this is revolutionary in the field, which provides the possibility of new ways to let those with ASD accurately perceive sensory signals to improve processing and increase decision making.

References

Centers for Disease Control and Prevention (CDC). (2022, June 3). Data and Statistics on Fragile X Syndrome. https://www.cdc.gov/ncbddd/fxs/data.html.

Henderson, E. (2023, Feb 17). Study reveals new clues to the underlying cause of FXS symptoms. News Medical Life Sciences. https://www.news-medical.net/news/20230217/Study-reveals-new-clues-to-the-underlying-cause-of-FXS-symptoms.aspx.

Kaufmann, W. E., Kidd, S. A., Andrews, H. F., Budimirovic, D. B., Esler, A., Haas-Givler, B., Stackhouse, T., Riley, C., Peacock, G., Sherman, S. L., Brown, W. T., & Berry-Kravis, E. (2017). Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment. Pediatrics, 139(Suppl 3), S194–S206. https://doi.org/10.1542/peds.2016-1159F

Mitchell, D.E., et al. (2023) Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome. PNAS. doi.org/10.1073/pnas.2208963120. World Health Organization. (2023, March 29). Autism. https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders#:~:text=It%20is%20estimated%20that%20worldwide,prevalence%20varies%20substantially%20across%20studies.