Mechanisms Driving the Emergence of Neuronal Hyperexcitability in Fragile X Syndrome

• Type of Material: Article
• Authors: Pernille Bulow, Emory University; Menahem Segal, Weizmann Institute of Science; Gary Bassell, Emory University
• Language: English
• Date: 2022-06-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms23116315
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 23
• Issue: 11
• Grant/Funding Information: This research was supported by NIH 1R01MH109026 (GJB).
• Keywords: MENTAL-RETARDATION PROTEIN; Chemistry, Multidisciplinary; Science & Technology; Life Sciences & Biomedicine; FMRP; homeostatic plasticity; POTASSIUM CHANNELS; HOMEOSTATIC PLASTICITY; SODIUM CURRENT; SYNAPTIC PLASTICITY; Physical Sciences; Biochemistry & Molecular Biology; DEPENDENT REGULATION; the Fragile X Messenger Ribonucleoprotein; FMR1; Fragile X Syndrome; GABA(A) RECEPTOR; ion channels; hyperexcitability; MOUSE MODEL; MESSENGER-RNA; DENDRITIC SPINES; Chemistry
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery

Abstract

Hyperexcitability is a shared neurophysiological phenotype across various genetic neuro-developmental disorders, including Fragile X syndrome (FXS). Several patient symptoms are associated with hyperexcitability, but a puzzling feature is that their onset is often delayed until their second and third year of life. It remains unclear how and why hyperexcitability emerges in neuro-developmental disorders. FXS is caused by the loss of FMRP, an RNA-binding protein which has many critical roles including protein synthesis-dependent and independent regulation of ion channels and receptors, as well as global regulation of protein synthesis. Here, we discussed recent literature uncovering novel mechanisms that may drive the progressive onset of hyperexcitability in the FXS brain. We discussed in detail how recent publications have highlighted defects in homeostatic plasticity, providing new insight on the FXS brain and suggest pharmacotherapeutic strategies in FXS and other neurodevelopmental disorders.