Ruby Watson

Background: Fragile X Syndrome (FXS) results from mutation in a single gene, Fmr1, and is the leading known cause of autism spectrum disorders (ASD), accounting for 5% of cases.¹ Fmr1 mutation prevents the gene from being expressed and results in a lack of fragile X messenger ribonucleoprotein.² Individuals with FXS present with intellectual impairments, auditory hypersensitivity and other atypical sensory functions, social deficits, and repetitive behaviors.^1,2,3 Imbalances in excitation-inhibition circuits in the brain have been indicated in ASD and FXS, although the roles of specific interneuron subtypes are still being explored.^1,3 Improving our understanding of the role these interneurons play in the pathology of FXS/ASD could allow for the development of therapies which improve the symptoms of this syndrome.¹ Previous studies focused on excitation-inhibition circuit imbalances resulting from hyper-excitation rather than hypo-inhibition.^1,3 However, post-mortem studies of individuals with FXS have consistently recorded low numbers of parvalbumin-expressing interneurons, which are involved in GABA-inhibitory signaling.¹ Thus, hypo-inhibition should be further investigated as a mechanistic cause of FXS.

Objective: In this narrative review, I explored recent research indicating that hypo-inhibition is a mechanistic cause of FXS and that interventions targeting hypo-inhibition in the mouse model help alleviate FXS symptoms.

Search Methods: An online search was conducted in PubMed from 2017 to 2023 using the following key word combination: “Fragile X Syndrome” AND “interneuron”.

Results: Parvalbumin interneurons and perineuronal nets, a feature of the extracellular matrix surrounding these interneurons, are hypo-expressed in Fmr1 knockout mice and are sufficient to produce FXS symptoms in the mouse model.⁴ Matrix-metalloproteinase-9 (MMP9) hyper-expression during neural development leads to presentation with FXS symptoms in the mouse model, while genetic restoration of MMP9 resulted in neural and behavioral development not different from wild type.⁵ During neural development in Fmr1 knockout mice, the TrkB receptor, normally found on wild type parvalbumin interneurons, is hyper-expressed while its agonist is hypo-expressed.⁶ Administration of a TrkB agonist during neural development resulted in wild type TrkB signaling and restored parvalbumin interneuron development, resulting in amelioration of FXS symptoms in the mouse model.⁶ Postnatally, reexpression of the Fmr1 gene in Fmr1 knockout mice restored density of parvalbumin interneurons and ameliorated FXS symptoms.⁷ In an additional study targeting postnatal treatment, Fmr1 knockout mice were observed to display a visual task learning deficit which was ameliorated by treatment with an agonist for the hM3Dq excitatory receptor of parvalbumin interneurons 30 minutes prior to learning sessions.⁸

Conclusion: The success of multiple treatment mechanisms targeting hypo-inhibition of parvalbumin interneurons in the mouse model demonstrates the role these interneurons play in the development of FXS and a potential therapeutic target for FXS.

Works Cited:

1. Nomura T. Interneuron Dysfunction and Inhibitory Deficits in Autism and Fragile X Syndrome. Cells. 2021;10(10):2610. doi:3390/cells10102610
2. Lee E, Lee J, Kim E. Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders. Biological Psychiatry. 2017;81(10):838-847. doi:10.1016/j.biopsych.2016.05.011
3. Razak KA, Binder DK, Ethell IM. Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome. Frontiers in Psychiatry. 2021;12:720752. doi:10.3389/fpsyt.2021.720752
4. Lovelace JW, Rais M, Palacios AR, Shuai XS, Bishay S, Popa O, Pirbhoy PS, Binder DK, Nelson DL, Ethell IM, Razak KA. Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome. Cerebral Cortex. 2020;30(3):969-988. doi:10.1093/cercor/bhz141
5. Wen TH, Afroz S, Reinhard SM, Palacios AR, Tapia K, Binder DK, Razak KA, Ethell IM. Genetic Reduction of Matrix Metalloproteinase-9 Promotes Formation of Perineuronal Nets Around Parvalbumin-Expressing Interneurons and Normalizes Auditory Cortex Responses in Developing Fmr1 Knock-Out Mice. Cerebral Cortex. 2018;28(11):3951-3964. doi:10.1093/cercor/bhx258
6. Nomura T, Musial TF, Marshall JJ, Zhu Y, Remmers CL, Xu J, Nicholson DA, Contractor A. Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome. Journal of Neuroscience. 2017;37(47):11298-11310. doi:10.1523/JNEUROSCI.2893-16.2017
7. Rais M, Lovelace JW, Shuai XS, Woodard W, Bishay S, Estrada L, Sharma AR, Nguy A, Kulinich A, Pirbhoy PS, Palacios AR, Nelson DL, Razak KA, Ethell IM. Functional consequences of postnatal interventions in a mouse model of Fragile X syndrome. Neurobiology of Disease. 2022;162:105577. doi:10.1016/j.nbd.2021.105577
8. Goel A, Cantu DA, Guifoyle J, Chaudhari GR, Newadkar A, Todisco B, de Alba D, Kourdougli N, Schmitt LM, Pedapati E, Erickson CA, Portera-Cailliau C. Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nature Neuroscience. 2018;21(10):1404-1411. doi:10.1038/s41593-018-0231-0